Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases

ABSTRACT

Provided herein are hydroxypyridone derivatives, for example, a compound of Formula I, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of International Patent ApplicationNo. PCT/US2011/038700, filed Jun. 1, 2011, which claims the benefit ofU.S. Provisional Application No. 61/350,431, filed Jun. 1, 2010; thedisclosure of each of which is incorporated herein by reference in itsentirety.

FIELD

Provided herein are hydroxypyridone derivatives, and pharmaceuticalcompositions thereof. Also provided herein are methods for treating,preventing, or ameliorating one or more symptoms of a proliferativedisease.

BACKGROUND

Hematologic or hematopoietic malignancies are cancers of the blood orbone marrow, including leukemia and lymphoma. Leukemia is characterizedby the uncontrolled accumulation of blood cells, which is categorizedinto four types: acute lymphocytic leukemia (ALL), acute myelogenousleukemia (AML), chronic lymphocytic leukemia (CLL), and chronicmyelogenous leukemia (CML). Acute leukemia is a rapidly progressingdisease that results in the accumulation of immature, functionless cellsin the marrow and blood. The marrow often stops producing enough normalred cells, white cells and platelets. On the other hand, chronicleukemia progresses more slowly and allows greater numbers of moremature, functional cells to be made. Chronic leukemias account for 11percent more cases than acute leukemias.

It was estimated that 245,225 people in the United States were livingwith, or were in remission from, leukemia in 2009. Leukemia was expectedto strike more than 10 times as many adults as children in 2009 (About44,790 adults compared with 3,509 children, aged 0-14 years). The mostcommon types of leukemia in adults are acute myelogenous leukemia (AML),with estimated 12,810 new cases in 2009, and chronic lymphocyticleukemia (CLL), with about 15,490 new cases in 2009. Chronic myelogenousleukemia (CML) was estimated to affect about 5,050 persons in 2009. Themost common type of leukemia in children is acute lymphocytic leukemia(ALL), which was estimated to affect about 5,760 persons in 2009.

While current chemotherapy can result in complete remissions, the longterm disease-free survival rate for leukemias, in particular AML, islow. For example, the survival rate for AML was estimated to be lessthan about 20% in 2009. Therefore, there is a clear and unmet need foreffective therapeutics for treatment of hematologic malignancies,including leukemias.

SUMMARY OF THE DISCLOSURE

Provided herein is a compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof;wherein:

Z is a bond, —O—, —S—, —S(O)—, —S(O₂)—, or —N(R⁸)—;

R¹ is hydrogen or —C(O)R²;

R² is (a) hydrogen or deuterium; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —OR^(1a), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), or—NR^(1a)S(O)₂NR^(1b)R^(1c);

R³ and R⁵ are each independently hydrogen, deuterium, or fluoro;

R⁴ is —COOH, —CH₂R^(4a), —CH(R^(4a))₂, or —C(R^(4a))₃; wherein R^(4a) ishydrogen, deuterium, fluoro, or hydroxyl;

R⁶ is hydrogen, deuterium, fluoro, or hydroxyl;

each R⁷ is independently (a) deuterium, halo, cyano, nitro, orguanidine; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), C(NR^(1a))NR^(1b)R^(1c),OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or

two R⁷ are linked together to form a bond, —O—, —NR⁸—, —S—, C₁₋₆alkylene, C₁₋₆ heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆heteroalkenylene;

R⁸ is independently (a) hydrogen or deuterium; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,deuterium, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or R^(1a) andR^(1c) together with the C and N atoms to which they are attached formheterocyclyl; or R^(1b) and R^(1c) together with the N atom to whichthey are attached form heterocyclyl;

m is an integer of 1, 2, 3, or 4; and

n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;

with the proviso that at least one of R¹, R³, R⁵, R⁶, R⁷, and R^(4a) isnot hydrogen,

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more substituents Q,where each Q is independently selected from (a) deuterium, cyano, halo,and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of whichis further optionally substituted with one or more, in one embodiment,one, two, three, or four, substituents Q^(a); and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heterocyclyl.

Also provided herein are pharmaceutical compositions comprising acompound disclosed herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; in combination with one or morepharmaceutically acceptable carriers.

Further provided herein is a method for treating, preventing, orameliorating one or more symptoms of a proliferative disease in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound disclosed herein, e.g., a compound ofFormula I, an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, oran isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

Additionally provided herein is a method of inhibiting the growth of acell, comprising the step of contacting the cell with a compoundprovided herein, e.g., a compound of Formula I, including an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows effects of 6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-ylbenzoate 338 on cancer cell lines after 72-hour treatment.

FIG. 2 shows effects of 6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-ylbenzoate 338 on osteosarcoma cell line Mos 1 after 72-hour treatment.

FIG. 3 shows effects of 6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-ylbenzoate 338 on cancer cell lines after 72-hour treatment.

FIG. 4 shows effects of 6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-ylbenzoate 338 on cancer cell lines after 72-hour treatment.

FIG. 5 shows effects of6-cyclohexyl-1-hydroxy-4-(trifluoromethyl)pyridin-2(1H)-one 54 on cancercell lines after 72-hour treatment.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, and pharmacology describedherein are those well known and commonly employed in the art. Unlessdefined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this disclosure belongs.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject, in one embodiment, a human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The term “therapeutically effective amount” are meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell,tissue, system, animal, or human, which is being sought by a researcher,veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, solvent, or encapsulating material. Inone embodiment, each component is “pharmaceutically acceptable” in thesense of being compatible with the other ingredients of a pharmaceuticalformulation, and suitable for use in contact with the tissue or organ ofhumans and animals without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%,4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer of a compound describedherein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “alkyl” refers to a linear or branched saturated monovalenthydrocarbon radical, wherein the alkyl may optionally be substitutedwith one or more substituents Q as described herein. For example, C₁₋₆alkyl refers to a linear saturated monovalent hydrocarbon radical of 1to 6 carbon atoms or a branched saturated monovalent hydrocarbon radicalof 3 to 6 carbon atoms. In certain embodiments, the alkyl is a linearsaturated monovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to15 (C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated monovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋₆ and branched C₃₋₆ alkyl groups are also referred as “loweralkyl.” Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl (including all isomeric forms), n-propyl,isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl,sec-butyl, t-butyl, pentyl (including all isomeric forms), and hexyl(including all isomeric forms).

The term “alkylene” refers to a linear or branched saturated divalenthydrocarbon radical, wherein the alkylene may optionally be substitutedwith one or more substituents Q as described herein. For example, C₁₋₆alkylene refers to a linear saturated divalent hydrocarbon radical of 1to 6 carbon atoms or a branched saturated divalent hydrocarbon radicalof 3 to 6 carbon atoms. In certain embodiments, the alkylene is a linearsaturated divalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branchedsaturated divalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15(C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein,linear C₁₋6 and branched C₃₋₆ alkylene groups are also referred as“lower alkylene.” Examples of alkylene groups include, but are notlimited to, methylene, ethylene, propylene (including all isomericforms), n-propylene, isopropylene, butylene (including all isomericforms), n-butylene, isobutylene, t-butylene, pentylene (including allisomeric forms), and hexylene (including all isomeric forms).

The term “heteroalkylene” refers to a linear or branched saturateddivalent hydrocarbon radical that contains one or more heteroatoms eachindependently selected from O, S, and N in the hydrocarbon chain. Forexample, C₁₋₆ heteroalkylene refers to a linear saturated divalenthydrocarbon radical of 1 to 6 carbon atoms or a branched saturateddivalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the heteroalkylene is a linear saturated divalenthydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15 (C₁₋₁₅), 1 to 10(C₁₋₁₀), or 1 to 6 (C₁₋₆) carbon atoms, or branched saturated divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ andbranched C₃₋₆ heteroalkylene groups are also referred as “lowerheteroalkylene.” Examples of heteroalkylene groups include, but are notlimited to, —CH₂O—, —CH₂OCH₂—, —CH₂CH₂O—, —CH₂NH—, —CH₂NHCH₂—,—CH₂CH₂NH—, —CH₂S—, —CH₂SCH₂—, and —CH₂CH₂S—. In certain embodiments,heteroalkylene may also be optionally substituted with one or moresubstituents Q as described herein.

The term “alkenyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon double bond(s). The alkenyl maybe optionally substituted with one or more substituents Q as describedherein. The term “alkenyl” embraces radicals having a “cis” or “trans”configuration or a mixture thereof, or alternatively, a “Z” or “E”configuration or a mixture thereof, as appreciated by those of ordinaryskill in the art. For example, C₂₋₆ alkenyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched monovalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groupsinclude, but are not limited to, ethenyl, propen-1-yl, propen-2-yl,allyl, butenyl, and 4-methylbutenyl.

The term “alkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, oneto five, in another embodiment, one, carbon-carbon double bond(s). Thealkenylene may be optionally substituted with one or more substituents Qas described herein. The term “alkenylene” embraces radicals having a“cis” or “trans” configuration or a mixture thereof, or alternatively, a“Z” or “E” configuration or a mixture thereof, as appreciated by thoseof ordinary skill in the art. For example, C₂₋₆ alkenylene refers to alinear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkenylene is a linear divalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenylene groupsinclude, but are not limited to, ethenylene, allylene, propenylene,butenylene, and 4-methylbutenylene.

The term “heteroalkenylene” refers to a linear or branched divalenthydrocarbon radical, which contains one or more, in one embodiment, oneto five, in another embodiment, one, carbon-carbon double bond(s), andwhich contains one or more heteroatoms each independently selected fromO, S, and N in the hydrocarbon chain. The heteroalkenylene may beoptionally substituted with one or more substituents Q as describedherein. The term “heteroalkenylene” embraces radicals having a “cis” or“trans” configuration or a mixture thereof, or alternatively, a “Z” or“E” configuration or a mixture thereof, as appreciated by those ofordinary skill in the art. For example, C₂₋₆ heteroalkenylene refers toa linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atomsor a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the heteroalkenylene is a linear divalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10(C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branched divalenthydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10(C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples of heteroalkenylenegroups include, but are not limited to, —CH═CHO—, —CH═CHOCH₂—,—CH═CHCH₂O—, —CH═CHS—, —CH═CHSCH₂—, —CH═CHCH₂S—, or —CH═CHCH₂NH—.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical, which contains one or more, in one embodiment, one to five, inanother embodiment, one, carbon-carbon triple bond(s). The alkynyl maybe optionally substituted with one or more substituents Q as describedherein. For example, C₂₋₆ alkynyl refers to a linear unsaturatedmonovalent hydrocarbon radical of 2 to 6 carbon atoms or a branchedunsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. Incertain embodiments, the alkynyl is a linear monovalent hydrocarbonradical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 10 (C₂₋₁₀), or 2 to 6(C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radical of 3to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbonatoms. Examples of alkynyl groups include, but are not limited to,ethynyl (—CCH), propynyl (including all isomeric forms, e.g., 1-propynyl(—CCCH₃) and propargyl (—CH₂CCH)), butynyl (including all isomericforms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including allisomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), andhexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl).

The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical,which may be optionally substituted with one or more substituents Q asdescribed herein. In one embodiment, cycloalkyl groups may be saturatedor unsaturated but non-aromatic, and/or bridged, and/or non-bridged,and/or fused bicyclic groups. In certain embodiments, the cycloalkyl hasfrom 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 10 (C₃₋₁₀), orfrom 3 to 7 (C₃₋₇) carbon atoms. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, andadamantyl.

The term “aryl” refers to a monovalent monocyclic aromatic group and/ormonovalent polycyclic aromatic group that contain at least one aromaticcarbon ring. In certain embodiments, the aryl has from 6 to 20 (C₆₋₂₀),from 6 to 15 (C₆₋₁₅), or from 6 to 10 (C₆₋₁₀) ring atoms. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl,fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, andterphenyl. Aryl also refers to bicyclic or tricyclic carbon rings, whereone of the rings is aromatic and the others of which may be saturated,partially unsaturated, or aromatic, for example, dihydronaphthyl,indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In certainembodiments, aryl may be optionally substituted with one or moresubstituents Q as described herein.

The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl groupsubstituted with one or more aryl groups. In certain embodiments, thearalkyl has from 7 to 30 (C₇₋₃₀), from 7 to 20 (C₇₋₂₀), or from 7 to 16(C₇₋₁₆) carbon atoms. Examples of aralkyl groups include, but are notlimited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certainembodiments, aralkyl are optionally substituted with one or moresubstituents Q as described herein.

The term “heteroaryl” refers to a monovalent monocyclic aromatic groupor monovalent polycyclic aromatic group that contain at least onearomatic ring, wherein at least one aromatic ring contains one or moreheteroatoms independently selected from O, S, and N in the ring.Heteroaryl groups are bonded to the rest of a molecule through thearomatic ring. Each ring of a heteroaryl group can contain one or two Oatoms, one or two S atoms, and/or one to four N atoms; provided that thetotal number of heteroatoms in each ring is four or less and each ringcontains at least one carbon atom. In certain embodiments, theheteroaryl has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms.Examples of monocyclic heteroaryl groups include, but are not limitedto, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments,heteroaryl may also be optionally substituted with one or moresubstituents Q as described herein.

The term “heterocyclyl” or “heterocyclic” refers to a monovalentmonocyclic non-aromatic ring system or monovalent polycyclic ring systemthat contains at least one non-aromatic ring, wherein one or more of thenon-aromatic ring atoms are heteroatoms independently selected from O,S, and N; and the remaining ring atoms are carbon atoms. In certainembodiments, the heterocyclyl or heterocyclic group has from 3 to 20,from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. Heterocyclyl groups are bonded to the rest of a moleculethrough the non-aromatic ring. In certain embodiments, the heterocyclylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay be fused or bridged, and in which nitrogen or sulfur atoms may beoptionally oxidized, nitrogen atoms may be optionally quaternized, andsome rings may be partially or fully saturated, or aromatic. Theheterocyclyl may be attached to the main structure at any heteroatom orcarbon atom which results in the creation of a stable compound. Examplesof such heterocyclic groups include, but are not limited to, azepinyl,benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl,benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl,benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromonyl,cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl,dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl,dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl,furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, heterocyclic may also beoptionally substituted with one or more substituents Q as describedherein.

The term “halogen”, “halide” or “halo” refers to fluorine, chlorine,bromine, and/or iodine.

The term “optionally substituted” is intended to mean that a group orsubstituent, such as an alkyl, alkylene, heteroalkylene, alkenyl,alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl,heteroaryl, or heterocyclyl group, may be substituted with one or moresubstituents Q, each of which is independently selected from, e.g., (a)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of which is furtheroptionally substituted with one or more, in one embodiment, one, two,three, or four, substituents Q^(a); and (b) deuterium, halo, cyano(—CN), nitro (—NO₂), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c),—C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a), —OC(O)OR^(a),—OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a),—OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d),—NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c),—NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c),—NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a), —S(O)₂R^(a),—S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b),R^(c), and R^(d) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ^(a); or (iii) R^(b) and R^(c) together with the N atom to which theyare attached form heteroaryl or heterocyclyl, optionally substitutedwith one or more, in one embodiment, one, two, three, or four,substituents Q^(a). As used herein, all groups that can be substitutedare “optionally substituted,” unless otherwise specified.

In one embodiment, each Q^(a) is independently selected from the groupconsisting of (a) deuterium, cyano, halo, and nitro; and (b) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen ordeuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f)and R^(g) together with the N atom to which they are attached formheteroaryl or heterocyclyl.

In certain embodiments, “optically active” and “enantiomerically active”refer to a collection of molecules, which has an enantiomeric excess ofno less than about 50%, no less than about 70%, no less than about 80%,no less than about 90%, no less than about 91%, no less than about 92%,no less than about 93%, no less than about 94%, no less than about 95%,no less than about 96%, no less than about 97%, no less than about 98%,no less than about 99%, no less than about 99.5%, or no less than about99.8%. In certain embodiments, the compound comprises about 95% or moreof one enantiomer and about 5% or less of the other enantiomer based onthe total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

The term “isotopically enriched” refers to a compound that contains anunnatural proportion of an isotope at one or more of the atoms thatconstitute such a compound. In certain embodiments, an isotopicallyenriched compound contains unnatural proportions of one or moreisotopes, including, but not limited to, hydrogen (¹H), deuterium (²H),tritium (³H), carbon-11 (¹¹C), carbon-12 (¹²C), carbon-13 (¹³C),carbon-14 (¹⁴C), nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O) oxygen-17(¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F), fluorine-18 (¹⁸F),phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32(³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36(³⁶S), chlorine-35 (³⁵Cl), chlorine-36 (³⁶Cl), chlorine-37 (³⁷Cl),bromine-79 (⁷⁹Br), bromine-81 (⁸¹Br), iodine-123 I) iodine-125 (¹²⁵I),iodine-127 (¹²⁷I), iodine-129 (¹²⁹I), and iodine-131 (¹³¹I. In certainembodiments, an isotopically enriched compound is in a stable form, thatis, non-radioactive. In certain embodiments, an isotopically enrichedcompound contains unnatural proportions of one or more isotopes,including, but not limited to, hydrogen (¹H), deuterium (²H), carbon-12(¹²C), carbon-13 (¹³C), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-16(¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F),phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S),sulfur-36 (³⁶S), chlorine-35 (³⁵Cl), chlorine-37 (³⁷Cl), bromine-79(⁷⁹Br), bromine-81 (⁸¹Br), and iodine-127 (¹²⁷I). In certainembodiments, an isotopically enriched compound is in an unstable form,that is, radioactive. In certain embodiments, an isotopically enrichedcompound contains unnatural proportions of one or more isotopes,including, but not limited to, tritium (³H), carbon-11 (¹¹C), carbon-14(¹⁴C), nitrogen-13 (¹³N), oxygen-14 (¹⁴O) oxygen-15 (¹⁵O), fluorine-18(¹⁸F), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S),chlorine-36 (³⁶Cl), iodine-123 (¹²³I), iodine-125 (¹²⁵I), iodine-129(¹²⁹I), and iodine-131 (131I). It will be understood that, in a compoundas provided herein, any hydrogen can be ²H, as example, or any carboncan be ¹³C, as example, or any nitrogen can be ¹⁵N, as example, or anyoxygen can be ¹⁸O, as example, where feasible according to the judgmentof one of skill.

The term “isotopic enrichment” refers to the percentage of incorporationof a less prevalent isotope (e.g., D for hydrogen) of an element at agiven position in a molecule in the place of a more prevalent isotope(e.g., ¹H for hydrogen) of the element. As used herein, when an atom ata particular position in a molecule is designated as a particular lessprevalent isotope, it is understood that the abundance of that isotopeat that position is substantially greater than its natural abundance.

The term “isotopic enrichment factor” refers the ratio between theisotopic abundance in an isotopically enriched compound and the naturalabundance of a specific isotope.

The term “hydrogen” or the symbol “H” refers to the composition ofnaturally occurring hydrogen isotopes, which include protium (¹H),deuterium (²H or D), and tritium (³H), in their natural abundances.Protium is the most common hydrogen isotope having a natural abundanceof more than 99.98%. Deuterium is a less prevalent hydrogen isotopehaving a natural abundance of about 0.0156%.

The term “deuterium enrichment” refers to the percentage ofincorporation of deuterium at a given position in a molecule in theplace of hydrogen. For example, deuterium enrichment of 1% at a givenposition means that 1% of molecules in a given sample contain deuteriumat the specified position. Because the naturally occurring distributionof deuterium is about 0.0156% on average, deuterium enrichment at anyposition in a compound synthesized using non-enriched starting materialsis about 0.0156% on average. As used herein, when a particular positionin an isotopically enriched compound is designated as having deuterium,it is understood that the abundance of deuterium at that position in thecompound is substantially greater than its natural abundance (0.0156%).

The term “carbon” or the symbol “C” refers to the composition ofnaturally occurring carbon isotopes, which include carbon-12 (¹²C) andcarbon-13 (¹³C) in their natural abundances. Carbon-12 is the mostcommon carbon isotope having a natural abundance of more than 98.89%.Carbon-13 is a less prevalent hydrogen isotope having a naturalabundance of about 1.11%.

The term “carbon-13 enrichment” or “¹³C enrichment” refers to thepercentage of incorporation of carbon-13 at a given position in amolecule in the place of carbon. For example, carbon-13 enrichment of10% at a given position means that 10% of molecules in a given samplecontain carbon-13 at the specified position. Because the naturallyoccurring distribution of carbon-13 is about 1.11% on average, carbon-13enrichment at any position in a compound synthesized using non-enrichedstarting materials is about 1.11% on average. As used herein, when aparticular position in an isotopically enriched compound is designatedas having carbon-13, it is understood that the abundance of carbon-13 atthat position in the compound is substantially greater than its naturalabundance (1.11%).

The terms “substantially pure” and “substantially homogeneous” meansufficiently homogeneous to appear free of readily detectable impuritiesas determined by standard analytical methods used by one of ordinaryskill in the art, including, but not limited to, thin layerchromatography (TLC), gel electrophoresis, high performance liquidchromatography (HPLC), gas chromatography (GC), nuclear magneticresonance (NMR), and mass spectrometry (MS); or sufficiently pure suchthat further purification would not detectably alter the physical,chemical, biological, and/or pharmacological properties, such asenzymatic and biological activities, of the substance. In certainembodiments, “substantially pure” or “substantially homogeneous” refersto a collection of molecules, wherein at least about 50%, at least about70%, at least about 80%, at least about 90%, at least about 95%, atleast about 98%, at least about 99%, or at least about 99.5% by weightof the molecules are a single compound, including a single enantiomer, aracemic mixture, a mixture of enantiomers, or a diastereomeric mixturethereof, as determined by standard analytical methods. As used herein,when an atom at a particular position in an isotopically enrichedmolecule is designated as a particular less prevalent isotope, amolecule that contains other than the designated isotope at thespecified position is an impurity with respect to the isotopicallyenriched compound. Thus, for a deuterated compound that has an atom at aparticular position designated as deuterium, a compound that contains aprotium at the same position is an impurity.

The term “solvate” refers to a complex or aggregate formed by one ormore molecules of a solute, e.g., a compound provided herein, and one ormore molecules of a solvent, which present in stoichiometric ornon-stoichiometric amount. Suitable solvents include, but are notlimited to, water, methanol, ethanol, n-propanol, isopropanol, andacetic acid. In certain embodiments, the solvent is pharmaceuticallyacceptable. In one embodiment, the complex or aggregate is in acrystalline form. In another embodiment, the complex or aggregate is ina noncrystalline form. Where the solvent is water, the solvate is ahydrate. Examples of hydrates include, but are not limited to, ahemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, andpentahydrate.

The term “proliferative disorder or disease” refers to unwanted cellproliferation of one or more subset of cells in a multicellular organismresulting in harm (i.e., discomfort or decreased life expectancy) to themulticellular organisms. A proliferative disorder or disease can occurin different types of animals and humans. For example, as used herein,“proliferative disorder or disease” includes neoplastic disorders andother proliferative disorders.

The term “neoplastic disorder or disease” or “cancer” refers to a tumorresulting from abnormal or uncontrolled cellular growth. Examples ofneoplastic disorders include, but are not limited to, hematopoieticdisorders, such as the myeloproliferative disorders, thrombocythemia,essential thrombocytosis (ET), angiogenic myeloid metaplasia,myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronicidiopathic myelofibrosis (IMF), polycythemia vera (PV), the cytopenias,and pre-malignant myelodysplastic syndromes; cancers, such as gliomacancers, lung cancers, breast cancers, colorectal cancers, prostatecancers, gastric cancers, esophageal cancers, colon cancers, pancreaticcancers, ovarian cancers, and hematologic malignancies.

The term “hematologic malignancy” refers to cancer of the body'sblood-forming and immune system—the bone marrow and lymphatic tissue.Examples of hematological malignancies include, for instance,myelodysplasia, lymphomas, leukemias, lymphomas (non-Hodgkin'slymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), andmyeloma, such as acute lymphocytic leukemia (ALL), acute myeloidleukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocyticleukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilicleukemia (CNL), acute undifferentiated leukemia (AUL), anaplasticlarge-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvenilemyelomonocyctic leukemia (JMML), adult T-cell ALL, AML with trilineagemyelodysplasia (AML/TMDS), mixed lineage leukemia (MLL), myelodysplasticsyndromes (MDSs), myeloproliferative disorders (MPD), and multiplemyeloma (MM).

The term “leukemia” refers to malignant neoplasms of the blood-formingtissues, including, but not limited to, chronic lymphocytic leukemia,chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloidleukemia and acute myeloblastic leukemia. The leukemia can be relapsed,refractory, or resistant to conventional therapy.

The term “relapsed” refers to a situation where a subject or a mammal,who has had a remission of cancer after therapy has a return of cancercells.

The term “refractory or resistant” refers to a circumstance where asubject or a mammal, even after intensive treatment, has residual cancercells in his body.

The term “drug resistance” refers to the condition when a disease doesnot respond to the treatment of a drug or drugs. Drug resistance can beeither intrinsic, which means the disease has never been responsive tothe drug or drugs, or it can be acquired, which means the disease ceasesresponding to a drug or drugs that the disease had previously respondedto. In certain embodiments, drug resistance is intrinsic. In certainembodiments, the drug resistance is acquired.

The phrase “an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof” has the same meaning as the phrase“an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variant of the compound referenced therein; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug of thecompound referenced therein, or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers,a mixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or isotopic variant of the compound referenced therein.”

Compounds

Provided herein are hydroxypyridone derivatives, and pharmaceuticalcompositions thereof. Also provided herein are methods for treating,preventing, or ameliorating one or more symptoms of a proliferativedisease.

In one embodiment, provided herein is a compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof;wherein:

Z is a bond, O, —S—, S(O)—, —S(O₂)—, or —N(R⁸)—;

R¹ is hydrogen or —C(O)R²;

R² is (a) hydrogen or deuterium; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl; or (c) —OR^(1a), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d),—NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), or—NR^(1a)S(O)₂NR^(1b)R^(1c);

R³ and R⁵ are each independently hydrogen, deuterium, or fluoro;

R⁴ is —COOH, —CH₂R^(4a), —CH(R^(4a))₂, or —C(R^(4a))₃; wherein R^(4a) ishydrogen, deuterium, fluoro, or hydroxyl;

R⁶ is hydrogen, deuterium, fluoro, or hydroxyl;

each R⁷ is independently (a) deuterium, halo, cyano, nitro, orguanidine; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R″,—C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a),—OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or

two R⁷ are linked together to form a bond, —O—, —NR⁸—, —S—, C₁₋₆alkylene, C₁₋₆ heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆heteroalkenylene;

R⁸ is independently (a) hydrogen or deuterium; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (c) —C(O)R^(1a), —C(O)OR^(1a),—C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a),—OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c),—OS(O)R^(1a), —OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c);

each R^(1a), R^(1b), R^(1c), and R^(1d) is independently hydrogen,deuterium, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl; or R^(1a) andR^(1c) together with the C and N atoms to which they are attached formheterocyclyl; or R^(1b) and R^(1c) together with the N atom to whichthey are attached form heterocyclyl;

m is an integer of 1, 2, 3, or 4; and

n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;

with the proviso that at least one of R¹, R³, R⁵, R⁶, R⁷, and R^(4a) isnot hydrogen,

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, andheterocyclyl is optionally substituted with one or more substituents Q,where each Q is independently selected from (a) deuterium, cyano, halo,and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each of whichis further optionally substituted with one or more, in one embodiment,one, two, three, or four, substituents Q^(a); and (c) —C(O)R^(a),—C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a),—OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c),—OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c),—NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen or deuterium; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, orheterocyclyl, each optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a); or (iii) R^(b)and R^(c) together with the N atom to which they are attached formheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q^(a);

wherein each Q^(a) is independently selected from the group consistingof (a) deuterium, cyano, halo, and nitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl,and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e), —C(O)NR^(f)R^(g),—C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e), —OC(O)OR^(e),—OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e), —OS(O)₂R^(e),—OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g), —NR^(e)C(O)R^(h),—NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g), —NR^(e)C(═NR^(h))NR^(f)R^(g),—NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h), —NR^(e)S(O)NR^(f)R^(g),—NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e), —S(O)₂R^(e),—S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein each R^(e), R^(f),R^(g), and R^(h) is independently (i) hydrogen or deuterium; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heterocyclyl.

In another embodiment, provided herein is a compound of Formula II:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R³, R⁴, R⁵, R⁶, R⁷, m,and n are each as defined herein.

In one embodiment, in Formula I or II, R⁴ is —CH₂R^(4a), —CH(R^(4a))₂,or —C(R^(4a))₃, wherein, in one embodiment, R^(4a) is deuterium, inanother embodiment, R^(4a) is fluoro, in yet another embodiment, R^(4a)is hydroxyl; and R¹, R³, R⁵, R⁶, R⁷, m, and n are each as definedherein. In another embodiment, in Formula I or II, R⁴ is —COOH; and R¹,R³, R⁵, R⁶, R⁷, m, and n are each as defined herein.

In one embodiment, in Formula I or II, one or more of R³, R⁵, and R⁶ isdeuterium, fluoro, or hydroxyl; and R¹, R⁴, R⁷, m, and n are each asdefined herein.

In certain embodiments, in Formula II, R¹ is hydrogen or —C(O)—C₆₋₁₄aryl; R³, R⁵, and R⁶ are hydrogen; R⁴ is C₁₋₆ alkyl; m is 2; and n is 0;where the alkyl and aryl are optionally substituted with one or moresubstituents Q.

In certain embodiments, in Formula II, R¹ is hydrogen or benzoyl; R³,R⁵, and R⁶ are hydrogen; R⁴ is methyl; m is 2; and n is 0; where themethyl and benzoyl are optionally substituted with one or moresubstituents Q.

In certain embodiments, in Formula II, R¹ is hydrogen or benzoyl; R³,R⁵, and

R⁶ are hydrogen; R⁴ is methyl or trifluoromethyl; m is 2; and n is 0.

In yet another embodiment, provided herein is a compound of Formula III:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R⁷, Z, m, and n are eachas defined herein.

In yet another embodiment, provided herein is a compound of FormulaIIIa:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R⁷, m, and n are each asdefined herein.

In yet another embodiment, provided herein is a compound of Formula IV:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein one or both of R³ and R⁵is deuterium or fluoro; and R⁷, Z, m, and n are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula IVa:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein one or both of R³ and R⁵is deuterium or fluoro; and R⁷, m, and n are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula V:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R⁴ is —CH₂R^(4a),—CH(R^(4a))₂, or —C(R^(4a))₃; and one or more of R^(4a) and R⁶ isdeuterium, fluoro, or hydroxyl; and R⁷, Z, m, and n are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula Va:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R⁴ is —CH₂R^(4a),—CH(R^(4a))₂, or —C(R^(4a))₃; and one or more of R^(4a) and R⁶ isdeuterium, fluoro, or hydroxyl; and R⁷, m, and n are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula VI:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers thereof,or an isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; wherein R¹, R³, R⁴, R⁵, and R⁶ areeach as defined herein.

The groups, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R^(1a), R^(1b), R^(1c),R^(1d), R^(4a), Z, m, and n in formulae described herein, includingFormulae I to VI and IIIa to Va, are further defined in the embodimentsdescribed herein. All combinations of the embodiments provided hereinfor such groups are within the scope of this disclosure.

In certain embodiments, R¹ is hydrogen. In certain embodiments, R¹ isdeuterium. In certain embodiments, R¹ is —C(O)R², wherein R² is asdefined herein. In certain embodiments, R¹ is —C(O)—C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R¹ is —C(O)—C₁₋₆ alkyl, optionally substituted with one ormore deuterium or halo. In certain embodiments, R¹ is —C(O)-methyl,—C(O)-ethyl, —C(O)-propyl, or —C(O)-butyl, optionally substituted withone, two, or three deuterium or fluoro. In certain embodiments, R¹ is—C(O)—C₆₋₁₄ aryl, optionally substituted with one or more substituentsQ. In certain embodiments, R¹ is benzoyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R² isdeuterium. In certain embodiments, R² is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is C₁₋₆ alkyl, optionally substituted with one, two, or three halo. Incertain embodiments, R² is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl). Incertain embodiments, R² is methyl, —CH₂D, —CHD₂, or —CD₃. In certainembodiments, R² is methyl, —CH₂F, —CHF₂, or —CF₃. In certainembodiments, R² is C₂₋₆ alkenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R² is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is C₃₋₇ cycloalkyl, optionally substituted with one or more substituentsQ. In certain embodiments, R² is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q. In certain embodiments, R² is phenyl,optionally substituted with one or more substituents Q. In certainembodiments, R² is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R² is benzyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R²is heteroaryl, optionally substituted with one or more substituents Q.In certain embodiments, R² is heterocyclyl, optionally substituted withone or more substituents Q.

In certain embodiments, R² is —OR^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R² is —OR^(1a), wherein R^(1a) is C₁₋₆alkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R² is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl,optionally substituted with one, two, or three halo. In certainembodiments, R² is NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each asdefined herein. In certain embodiments, R² is —NR^(1a)C(O)R^(1d),wherein R^(1a) and R^(1d) are each as defined herein. In certainembodiments, R² is —NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R² is—NR^(1a)C(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein. In certain embodiments, R² isNR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a), R^(1b), R^(1c), andR^(1d) are each as defined herein. In certain embodiments, R² is—NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R² is —NR^(1a)S(O)₂R^(1d), whereinR^(1a) and R^(1d) are each as defined herein. In certain embodiments, R²is —NR^(1a)S(O)NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) areeach as defined herein. In certain embodiments, R² is—NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b), and R^(1c) are eachas defined herein.

In certain embodiments, R³ is hydrogen. In certain embodiments, R³ isdeuterium. In certain embodiments, R³ is fluoro.

In certain embodiments, R⁴ is —COOH. In certain embodiments, R⁴ is—CH₂R^(4a), wherein R^(4a) is as defined herein. In certain embodiments,R⁴ is —CH(R^(4a))₂, wherein each R^(4a) is as defined herein. In certainembodiments, R⁴ is —C(R^(4a))₃, wherein each R^(4a) is as definedherein. In certain embodiments, R⁴ is —CH₂D, —CHD₂, or —CD₃. In certainembodiments, R⁴ is —CH₂F, —CHF₂, or —CF₃. In certain embodiments, R⁴ is—CH₂OH, —CH(OH)₂ (i.e., CHO), or —C(OH)₃ (i.e., COOH).

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ isdeuterium. In certain embodiments, R⁵ is fluoro.

In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ isdeuterium. In certain embodiments, R⁶ is fluoro. In certain embodiments,R⁶ is hydroxyl.

In certain embodiments, R⁷ is deuterium. In certain embodiments, R⁷ ishalo. In certain embodiments, R⁷ is fluoro or chloro. In certainembodiments, R⁷ is cyano or —¹³CN. In certain embodiments, R⁷ is nitro.In certain embodiments, R⁷ is guanidine. In certain embodiments, R⁷ isC₁₋₆ alkyl, optionally substituted with one or more substituents Q. Incertain embodiments, R⁷ is C₁₋₆ alkyl, optionally substituted with one,two, or three halo. In certain embodiments, R⁷ is methyl, ethyl, propyl(e.g., n-propyl or isopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl,or t-butyl), pentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R⁷ is methyl, —CH₂D, —CHD₂,or —CD₃. In certain embodiments, R⁷ is C₂₋₆ alkenyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁷is C₂₋₆ alkynyl, optionally substituted with one or more substituents Q.In certain embodiments, R⁷ is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁷ is C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R⁷ is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R⁷ is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R⁷ is heterocyclyl, optionally substituted with one or moresubstituents Q.

In certain embodiments, R⁷ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁷ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁷ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁷ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R⁷ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁷ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁷ is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁷ is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R⁷ is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R⁷ is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁷ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R⁷ is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁷ is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R⁷ is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁷ is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁷ is NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁷ is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R⁷ is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁷ is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R⁷ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R⁷ is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R⁷ is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁷ is —NR^(1a)S(O)NR^(1b)R^(1c), Kwherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R⁷ is —NR^(1a)S(O)₂NR^(1b)R^(1c) wherein R^(1a),R^(1b), and R^(1c) are each as defined herein. In certain embodiments,R⁷ is —SR^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R⁷ is —SR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁷is —SR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substituted withone, two, or three halo. In certain embodiments, R⁷ is —S(O)R^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R⁷ is—S(O)₂R^(1a), wherein R^(1a) is as defined herein. In certainembodiments, R⁷ is —S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁷ is—S(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein.

In certain embodiments, two R⁷ are linked together to form a bond. Incertain embodiments, two R⁷ are linked together to form —O—. In certainembodiments, two R⁷ are linked together to form —NR⁸—, where R⁸ is asdefined herein. In certain embodiments, two R⁷ are linked together toform —S—. In certain embodiments, two R⁷ are linked together to formC₁₋₆ alkylene, optionally substituted with one or more substituents Q.In certain embodiments, two R⁷ are linked together to form methylene,ethylene, or propylene, each optionally substituted with one or moresubstituents Q. In certain embodiments, two R⁷ are linked together toform C₁₋₆ heteroalkylene, optionally substituted with one or moresubstituents Q. In certain embodiments, two R⁷ are linked together toform C₂₋₆ alkenylene, optionally substituted with one or moresubstituents Q. In certain embodiments, two R⁷ are linked together toform C₂₋₆ heteroalkenylene, optionally substituted with one or moresubstituents Q. In certain embodiments, two R⁷ are linked together toform a fused ring. In certain embodiments, two R⁷ are linked together toform a bridged ring. In certain embodiments, two R⁷ are linked togetherto form a spiro ing.

In certain embodiments, R⁸ is hydrogen. In certain embodiments, R⁸ isdeuterium. In certain embodiments, R⁸ is C₁₋₆ alkyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁸is C₁₋₆ alkyl, optionally substituted with one, two, or three halo. Incertain embodiments, R⁸ is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), pentyl(e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, or 2,2-dimethylpropyl). Incertain embodiments, R⁸ is methyl, —CH₂D, —CHD₂, or —CD₃. In certainembodiments, R⁸ is C₂₋₆ alkenyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁸ is C₂₋₆ alkynyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R⁸is C₃₋₇ cycloalkyl, optionally substituted with one or more substituentsQ. In certain embodiments, R⁸ is C₆₋₁₄ aryl, optionally substituted withone or more substituents Q. In certain embodiments, R⁸ is C₇₋₁₅ aralkyl,optionally substituted with one or more substituents Q. In certainembodiments, R⁸ is heteroaryl, optionally substituted with one or moresubstituents Q. In certain embodiments, R⁸ is heterocyclyl, optionallysubstituted with one or more substituents Q.

In certain embodiments, R⁸ is —C(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁸ is —C(O)OR^(1a), wherein R^(1a) is asdefined herein. In certain embodiments, R⁸ is —C(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —C(NR^(1a))NR^(1b)R^(1c), wherein R^(1a), R^(1b), andR^(1c) are each as defined herein. In certain embodiments, R⁸ is—OR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁸ is —OR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁸ is —OR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁸ is —OC(O)R^(1a), wherein R^(1a)is as defined herein. In certain embodiments, R⁸ is —OC(O)OR^(1a),wherein R^(1a) is as defined herein. In certain embodiments, R⁸ is—OC(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁸ is —OC(═NR^(1a))NR^(1b)R^(1c),wherein R^(1a), R^(1b), and R^(1c) are each as defined herein. Incertain embodiments, R⁸ is —OS(O)R^(1a), wherein R^(1a) is as definedherein. In certain embodiments, R⁸ is —OS(O)₂R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R⁸ is —OS(O)NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —OS(O)₂NR^(1b)R^(1c), wherein R^(1b) and R^(1c) areeach as defined herein. In certain embodiments, R⁸ is NR^(1b)R^(1c),wherein R^(1b) and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)C(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R⁸ is—NR^(1a)C(O)OR^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁸ is —NR^(1a)C(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), wherein R^(1a),R^(1b), R^(1c), and R^(1d) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)S(O)R^(1d), wherein R^(1a) and R^(1d) areeach as defined herein. In certain embodiments, R⁸ is—NR^(1a)S(O)₂R^(1d), wherein R^(1a) and R^(1d) are each as definedherein. In certain embodiments, R⁸ is —NR^(1a)S(O)NR^(1b)R^(1c), whereinR^(1a), R^(1b), and R^(1c) are each as defined herein. In certainembodiments, R⁸ is —NR^(1a)S(O)₂NR^(1b)R^(1c), wherein R^(1a), R^(1b),and R^(1c) are each as defined herein. In certain embodiments, R⁸ is—SR^(1a), wherein R^(1a) is as defined herein. In certain embodiments,R⁸ is —SR^(1a), wherein R^(1a) is C₁₋₆ alkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R⁸ is —SR^(1a),wherein R^(1a) is C₁₋₆ alkyl, optionally substituted with one, two, orthree halo. In certain embodiments, R⁸ is —S(O)R^(1a), wherein R^(1a) isas defined herein. In certain embodiments, R⁸ is —S(O)₂R^(1a), whereinR^(1a) is as defined herein. In certain embodiments, R⁸ is—S(O)NR^(1b)R^(1c), wherein R^(1b) and R^(1c) are each as definedherein. In certain embodiments, R⁸ is —S(O)₂NR^(1b)R^(1c), whereinR^(1b) and R^(1c) are each as defined herein.

In certain embodiments, Z is a bond. In certain embodiments, Z is —O—.In certain embodiments, Z is —S—. In certain embodiments, Z is —S(O)—.In certain embodiments, Z is —S(O₂)—. In certain embodiments, Z is—N(R⁸)—, where R⁸ is as defined herein. In certain embodiments, Z is—NH—. In certain embodiments, Z is —N(C(O)R^(1a))—, where R^(1a) is asdefined herein. In certain embodiments, Z is —N(C(O)C₁₋₆ alkyl)-. Incertain embodiments, Z is —N(C(O)CH₃)—.

In certain embodiments, m is 1. In certain embodiments, m is 2. Incertain embodiments, m is 3. In certain embodiments, m is 4.

In certain embodiments, n is 0. In certain embodiments, n is 1. Incertain embodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 5. In certainembodiments, n is 6. In certain embodiments, n is 7.

In certain embodiments, R^(1a) is hydrogen. In certain embodiments,R^(1a) is deuterium. In certain embodiments, R^(1a) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1a) is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), orpentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1a) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1a) is C₂₋₆ alkenyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1a) is C₂₋₆alkynyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(1a) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1a) is C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(1a) is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1a) is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1a) is heterocyclyl, optionally substituted with one ormore substituents Q.

In certain embodiments, R^(1b) is hydrogen. In certain embodiments,R^(1b) is deuterium. In certain embodiments, R^(1b) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), orpentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1b) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1b) is C₂₋₆ alkenyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1b) is C₂₋₆alkynyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(1b) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1b) is C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1b) is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1b) is heterocyclyl, optionally substituted with one ormore substituents Q.

In certain embodiments, R^(1c) is hydrogen. In certain embodiments,R^(1c) is deuterium. In certain embodiments, R^(1c) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1c) is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), orpentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1c) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1c) is C₂₋₆ alkenyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1c) is C₂₋₆alkynyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(1c) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1c) is C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(1c) is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1c) is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1c) is heterocyclyl, optionally substituted with one ormore substituents Q.

In certain embodiments, R^(1b) and R^(1c) together with the N atom towhich they are attached independently form heteroaryl, optionallysubstituted with one or more substituents Q. In certain embodiments,R^(1b) and R^(1c) together with the N atom to which they are attachedindependently form heterocyclyl, optionally substituted with one or moresubstituents Q.

In certain embodiments, R^(1d) is hydrogen. In certain embodiments,R^(1d) is deuterium. In certain embodiments, R^(1d) is C₁₋₆ alkyl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is methyl, ethyl, propyl (e.g., n-propyl orisopropyl), butyl (e.g., n-butyl, 2-butyl, isobutyl, or t-butyl), orpentyl (e.g., n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, or2,2-dimethylpropyl). In certain embodiments, R^(1d) is methyl, ethyl,isopropyl, isobutyl, t-butyl, 1,1-dimethylpropyl, or 2,2-dimethylpropyl.In certain embodiments, R^(1d) is C₂₋₆ alkenyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1d) is C₂₋₆alkynyl, optionally substituted with one or more substituents Q. Incertain embodiments, R^(1d) is C₃₋₇ cycloalkyl, optionally substitutedwith one or more substituents Q. In certain embodiments, R^(1d) is C₆₋₁₄aryl, optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is C₇₋₁₅ aralkyl, optionally substituted with one ormore substituents Q. In certain embodiments, R^(1d) is heteroaryl,optionally substituted with one or more substituents Q. In certainembodiments, R^(1d) is heterocyclyl, optionally substituted with one ormore substituents Q.

In one embodiment, provided herein is a compound selected from the groupconsisting of:

Cmpd# R¹ R³ R⁴ R⁵ R⁶  1 H D CH₃ H H  2 H H CH₃ D H  3 H D CH₃ D H  4 H FCH₃ H H  5 H F CH₃ D H  6 H H CH₃ F H  7 H D CH₃ F H  8 H F CH₃ F H  9 HH CH₂D H H  10 H D CH₂D H H  11 H H CH₂D D H  12 H D CH₂D D H  13 H FCH₂D H H  14 H F CH₂D D H  15 H H CH₂D F H  16 H D CH₂D F H  17 H F CH₂DF H  18 H H CHD₂ H H  19 H D CHD₂ H H  20 H H CHD₂ D H  21 H D CHD₂ D H 22 H F CHD₂ H H  23 H F CHD₂ D H  24 H H CHD₂ F H  25 H D CHD₂ F H  26H F CHD₂ F H  27 H H CD₃ H H  28 H D CD₃ H H  29 H H CD₃ D H  30 H D CD₃D H  31 H F CD₃ H H  32 H F CD₃ D H  33 H H CD₃ F H  34 H D CD₃ F H  35H F CD₃ F H  36 H H CH₂F H H  37 H D CH₂F H H  38 H H CH₂F D H  39 H DCH₂F D H  40 H F CH₂F H H  41 H F CH₂F D H  42 H H CH₂F F H  43 H D CH₂FF H  44 H F CH₂F F H  45 H H CHF₂ H H  46 H D CHF₂ H H  47 H H CHF₂ D H 48 H D CHF₂ D H  49 H F CHF₂ H H  50 H F CHF₂ D H  51 H H CHF₂ F H  52H D CHF₂ F H  53 H F CHF₂ F H  54 H H CF₃ H H  55 H D CF₃ H H  56 H HCF₃ D H  57 H D CF₃ D H  58 H F CF₃ H H  59 H F CF₃ D H  60 H H CF₃ F H 61 H D CF₃ F H  62 H F CF₃ F H  63 H H CH₂OH H H  64 H D CH₂OH H H  65H H CH₂OH D H  66 H D CH₂OH D H  67 H F CH₂OH H H  68 H F CH₂OH D H  69H H CH₂OH F H  70 H D CH₂OH F H  71 H F CH₂OH F H  72 H H COOH H H  73 HD COOH H H  74 H H COOH D H  75 H D COOH D H  76 H F COOH H H  77 H FCOOH D H  78 H H COOH F H  79 H D COOH F H  80 H F COOH F H  81 H H CH₃H D  82 H D CH₃ H D  83 H H CH₃ D D  84 H D CH₃ D D  85 H F CH₃ H D  86H F CH₃ D D  87 H H CH₃ F D  88 H D CH₃ F D  89 H F CH₃ F D  90 H H CH₂DH D  91 H D CH₂D H D  92 H H CH₂D D D  93 H D CH₂D D D  94 H F CH₂D H D 95 H F CH₂D D D  96 H H CH₂D F D  97 H D CH₂D F D  98 H F CH₂D F D  99H H CHD₂ H D 100 H D CHD₂ H D 101 H H CHD₂ D D 102 H D CHD₂ D D 103 H FCHD₂ H D 104 H F CHD₂ D D 105 H H CHD₂ F D 106 H D CHD₂ F D 107 H F CHD₂F D 108 H H CD₃ H D 109 H D CD₃ H D 110 H H CD₃ D D 111 H D CD₃ D D 112H F CD₃ H D 113 H F CD₃ D D 114 H H CD₃ F D 115 H D CD₃ F D 116 H F CD₃F D 117 H H CH₂F H D 118 H D CH₂F H D 119 H H CH₂F D D 120 H D CH₂F D D121 H F CH₂F H D 122 H F CH₂F D D 123 H H CH₂F F D 124 H D CH₂F F D 125H F CH₂F F D 126 H H CHF₂ H D 127 H D CHF₂ H D 128 H H CHF₂ D D 129 H DCHF₂ D D 130 H F CHF₂ H D 131 H F CHF₂ D D 132 H H CHF₂ F D 133 H D CHF₂F D 134 H F CHF₂ F D 135 H H CF₃ H D 136 H D CF₃ H D 137 H H CF₃ D D 138H D CF₃ D D 139 H F CF₃ H D 140 H F CF₃ D D 141 H H CF₃ F D 142 H D CF₃F D 143 H F CF₃ F D 144 H H CH₂OH H D 145 H D CH₂OH H D 146 H H CH₂OH DD 147 H D CH₂OH D D 148 H F CH₂OH H D 149 H F CH₂OH D D 150 H H CH₂OH FD 151 H D CH₂OH F D 152 H F CH₂OH F D 153 H H COOH H D 154 H D COOH H D155 H H COOH D D 156 H D COOH D D 157 H F COOH H D 158 H F COOH D D 159H H COOH F D 160 H D COOH F D 161 H F COOH F D 162 H H CH₃ H F 163 H DCH₃ H F 164 H H CH₃ D F 165 H D CH₃ D F 166 H F CH₃ H F 167 H F CH₃ D F168 H H CH₃ F F 169 H D CH₃ F F 170 H F CH₃ F F 171 H H CH₂D H F 172 H DCH₂D H F 173 H H CH₂D D F 174 H D CH₂D D F 175 H F CH₂D H F 176 H F CH₂DD F 177 H H CH₂D F F 178 H D CH₂D F F 179 H F CH₂D F F 180 H H CHD₂ H F181 H D CHD₂ H F 182 H H CHD₂ D F 183 H D CHD₂ D F 184 H F CHD₂ H F 185H F CHD₂ D F 186 H H CHD₂ F F 187 H D CHD₂ F F 188 H F CHD₂ F F 189 H HCD₃ H F 190 H D CD₃ H F 191 H H CD₃ D F 192 H D CD₃ D F 193 H F CD₃ H F194 H F CD₃ D F 195 H H CD₃ F F 196 H D CD₃ F F 197 H F CD₃ F F 198 H HCH₂F H F 199 H D CH₂F H F 200 H H CH₂F D F 201 H D CH₂F D F 202 H F CH₂FH F 203 H F CH₂F D F 204 H H CH₂F F F 205 H D CH₂F F F 206 H F CH₂F F F207 H H CHF₂ H F 208 H D CHF₂ H F 209 H H CHF₂ D F 210 H D CHF₂ D F 211H F CHF₂ H F 212 H F CHF₂ D F 213 H H CHF₂ F F 214 H D CHF₂ F F 215 H FCHF₂ F F 216 H H CF₃ H F 217 H D CF₃ H F 218 H H CF₃ D F 219 H D CF₃ D F220 H F CF₃ H F 221 H F CF₃ D F 222 H H CF₃ F F 223 H D CF₃ F F 224 H FCF₃ F F 225 H H CH₂OH H F 226 H D CH₂OH H F 227 H H CH₂OH D F 228 H DCH₂OH D F 229 H F CH₂OH H F 230 H F CH₂OH D F 231 H H CH₂OH F F 232 H DCH₂OH F F 233 H F CH₂OH F F 234 H H COOH H F 235 H D COOH H F 236 H HCOOH D F 237 H D COOH D F 238 H F COOH H F 239 H F COOH D F 240 H H COOHF F 241 H D COOH F F 242 H F COOH F F 243 H H CH₃ H OH 244 H D CH₃ H OH245 H H CH₃ D OH 246 H D CH₃ D OH 247 H F CH₃ H OH 248 H F CH₃ D OH 249H H CH₃ F OH 250 H D CH₃ F OH 251 H F CH₃ F OH 252 H H CH₂D H OH 253 H DCH₂D H OH 254 H H CH₂D D OH 255 H D CH₂D D OH 256 H F CH₂D H OH 257 H FCH₂D D OH 258 H H CH₂D F OH 259 H D CH₂D F OH 260 H F CH₂D F OH 261 H HCHD₂ H OH 262 H D CHD₂ H OH 263 H H CHD₂ D OH 264 H D CHD₂ D OH 265 H FCHD₂ H OH 266 H F CHD₂ D OH 267 H H CHD₂ F OH 268 H D CHD₂ F OH 269 H FCHD₂ F OH 270 H H CD₃ H OH 271 H D CD₃ H OH 272 H H CD₃ D OH 273 H D CD₃D OH 274 H F CD₃ H OH 275 H F CD₃ D OH 276 H H CD₃ F OH 277 H D CD₃ F OH278 H F CD₃ F OH 279 H H CH₂F H OH 280 H D CH₂F H OH 281 H H CH₂F D OH282 H D CH₂F D OH 283 H F CH₂F H OH 284 H F CH₂F D OH 285 H H CH₂F F OH286 H D CH₂F F OH 287 H F CH₂F F OH 288 H H CHF₂ H OH 289 H D CHF₂ H OH290 H H CHF₂ D OH 291 H D CHF₂ D OH 292 H F CHF₂ H OH 293 H F CHF₂ D OH294 H H CHF₂ F OH 295 H D CHF₂ F OH 296 H F CHF₂ F OH 297 H H CF₃ H OH298 H D CF₃ H OH 299 H H CF₃ D OH 300 H D CF₃ D OH 301 H F CF₃ H OH 302H F CF₃ D OH 303 H H CF₃ F OH 304 H D CF₃ F OH 305 H F CF₃ F OH 306 H HCH₂OH H OH 307 H D CH₂OH H OH 308 H H CH₂OH D OH 309 H D CH₂OH D OH 310H F CH₂OH H OH 311 H F CH₂OH D OH 312 H H CH₂OH F OH 313 H D CH₂OH F OH314 H F CH₂OH F OH 315 H H COOH H OH 316 H D COOH H OH 317 H H COOH D OH318 H D COOH D OH 319 H F COOH H OH 320 H F COOH D OH 321 H H COOH F OH322 H D COOH F OH 323 H F COOH F OHand enantiomers, mixtures of enantiomers, mixtures of two or morediastereomers, tautomers, mixtures of two or more tautomers, or isotopicvariants thereof or pharmaceutically acceptable salts, solvates,hydrates, or prodrugs thereof.

In another embodiment, provided herein is a compound selected from thegroup consisting of:

and enantiomers, mixtures of enantiomers, mixtures of two or morediastereomers, tautomers, mixtures of two or more tautomers, or isotopicvariants thereof or pharmaceutically acceptable salts, solvates,hydrates, or prodrugs thereof.

In yet another embodiment, provided herein is6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yl benzoate 338.

In certain embodiments, the compound provided herein isdeuterium-enriched. In certain embodiments, the compound provided hereinis carbon-13 enriched. In certain embodiments, the compound providedherein is carbon-14 enriched. In certain embodiments, the compoundprovided herein contains one or more less prevalent isotopes for otherelements, including, but not limited to, ¹⁵N for nitrogen; ¹⁷O or ¹⁸Ofor oxygen, and ³³S, ³⁴S, or ³⁶S for sulfur.

In certain embodiments, the compound provided herein has an isotopicenrichment factor of no less than about 5, no less than about 10, noless than about 20, no less than about 30, no less than about 40, noless than about 50, no less than about 60, no less than about 70, noless than about 80, no less than about 90, no less than about 100, noless than about 200, no less than about 500, no less than about 1,000,no less than about 2,000, no less than about 5,000, or no less thanabout 10,000. In any events, however, an isotopic enrichment factor fora specified isotope is no greater than the maximum isotopic enrichmentfactor for the specified isotope, which is the isotopic enrichmentfactor when a compound at a given position is 100% enriched with thespecified isotope. Thus, the maximum isotopic enrichment factor isdifferent for different isotopes. The maximum isotopic enrichment factoris 6410 for deuterium and 90 for carbon-13.

In certain embodiments, the compound provided herein has a deuteriumenrichment factor of no less than about 64 (about 1% deuteriumenrichment), no less than about 130 (about 2% deuterium enrichment), noless than about 320 (about 5% deuterium enrichment), no less than about640 (about 10% deuterium enrichment), no less than about 1,300 (about20% deuterium enrichment), no less than about 3,200 (about 50% deuteriumenrichment), no less than about 4,800 (about 75% deuterium enrichment),no less than about 5,130 (about 80% deuterium enrichment), no less thanabout 5,450 (about 85% deuterium enrichment), no less than about 5,770(about 90% deuterium enrichment), no less than about 6,090 (about 95%deuterium enrichment), no less than about 6,220 (about 97% deuteriumenrichment), no less than about 6,280 (about 98% deuterium enrichment),no less than about 6,350 (about 99% deuterium enrichment), or no lessthan about 6,380 (about 99.5% deuterium enrichment). The deuteriumenrichment can be determined using conventional analytical methods knownto one of ordinary skill in the art, including mass spectrometry andnuclear magnetic resonance spectroscopy.

In certain embodiments, the compound provided herein has a carbon-13enrichment factor of no less than about 1.8 (about 2% carbon-13enrichment), no less than about 4.5 (about 5% carbon-13 enrichment), noless than about 9 (about 10% carbon-13 enrichment), no less than about18 (about 20% carbon-13 enrichment), no less than about 45 (about 50%carbon-13 enrichment), no less than about 68 (about 75% carbon-13enrichment), no less than about 72 (about 80% carbon-13 enrichment), noless than about 77 (about 85% carbon-13 enrichment), no less than about81 (about 90% carbon-13 enrichment), no less than about 86 (about 95%carbon-13 enrichment), no less than about 87 (about 97% carbon-13enrichment), no less than about 88 (about 98% carbon-13 enrichment), noless than about 89 (about 99% carbon-13 enrichment), or no less thanabout 90 (about 99.5% carbon-13 enrichment). The carbon-13 enrichmentcan be determined using conventional analytical methods known to one ofordinary skill in the art, including mass spectrometry and nuclearmagnetic resonance spectroscopy.

In certain embodiments, at lease one of the atoms of the compoundprovided herein, as specified as isotopically enriched, has isotopicenrichment of no less than about 1%, no less than about 2%, no less thanabout 5%, no less than about 10%, no less than about 20%, no less thanabout 50%, no less than about 70%, no less than about 80%, no less thanabout 90%, or no less than about 98%. In certain embodiments, the atomsof the compound provided herein, as specified as isotopically enriched,have isotopic enrichment of no less than about 1%, no less than about2%, no less than about 5%, no less than about 10%, no less than about20%, no less than about 50%, no less than about 70%, no less than about80%, no less than about 90%, or no less than about 98%. In any events,the isotopic enrichment of the isotopically enriched atom of thecompound provided herein is no less than the natural abundance of theisotope specified.

In certain embodiments, at lease one of the atoms of the compoundprovided herein, as specified as deuterium-enriched, has deuteriumenrichment of no less than about 1%, no less than about 2%, no less thanabout 5%, no less than about 10%, no less than about 20%, no less thanabout 50%, no less than about 70%, no less than about 80%, no less thanabout 90%, or no less than about 98%. In certain embodiments, the atomsof the compound provided herein, as specified as deuterium-enriched,have deuterium enrichment of no less than about 1%, no less than about2%, no less than about 5%, no less than about 10%, no less than about20%, no less than about 50%, no less than about 70%, no less than about80%, no less than about 90%, or no less than about 98%.

In certain embodiments, at lease one of the atoms of the compoundprovided herein, as specified as ¹³C-enriched, has carbon-13 enrichmentof no less than about 2%, no less than about 5%, no less than about 10%,no less than about 20%, no less than about 50%, no less than about 70%,no less than about 80%, no less than about 90%, or no less than about98%. In certain embodiments, the atoms of the compound provided herein,as specified as ¹³C-enriched, have carbon-13 enrichment of no less thanabout 1%, no less than about 2%, no less than about 5%, no less thanabout 10%, no less than about 20%, no less than about 50%, no less thanabout 70%, no less than about 80%, no less than about 90%, or no lessthan about 98%.

In certain embodiments, the compound provided herein is isolated orpurified. In certain embodiments, the compound provided herein has apurity of at least about 50%, at least about 70%, at least about 80%, atleast about 90%, at least about 95%, at least about 98%, at least about99%, or at least about 99.5% by weight.

The compounds provided herein are intended to encompass all possiblestereoisomers, unless a particular stereochemistry is specified. Wherethe compound provided herein contains an alkenyl or alkenylene group,the compound may exist as one or mixture of geometric cis/trans (or Z/E)isomers. Where structural isomers are interconvertible, the compound mayexist as a single tautomer or a mixture of tautomers. This can take theform of proton tautomerism in the compound that contains, for example,an imino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. As such, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent, for compounds that undergo epimerization invivo, to administration of the compound in its (5) form. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude synthesis from a suitable optically pure precursor, asymmetricsynthesis from achiral starting materials, or resolution of anenantiomeric mixture, for example, chiral chromatography,recrystallization, resolution, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolamine,diethylamine, dimethylamine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

In certain embodiments, the compound provided herein is anethanolaminium salt.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

Methods of Synthesis

The compounds provided herein can be prepared, isolated, or obtained byany method known to one of skill in the art. For an example, a compoundof Formula I can be prepared according to the methods described in U.S.Pat. Nos. 3,883,545 and 3,972,888, the disclosure of each of which isincorporated herein by reference in its entirety.

In certain embodiments, a compound of Formula I is synthesized accordingto the synthetic procedures as shown in Scheme I.

Compound S1 is condensed with compound S2 to form compound S3, wherein Lis a leaving group, including, but not limited to chloro, bromo, andester, and R^(L) is C₁₋₆ alkyl, including methyl, ethyl, and t-butyl.Compound S3 is then coupled with compound S4 to form compound S5, whichis treated with hydroxyamine or a salt of hydroxyamine, including, butnot limited to hydrochloride, hydrobromide, and sulfate, to formcompound S6. Compound S6 is treated with R¹L to form a compound ofFormula I, where L is a leaving group as defined herein.

In one embodiment, an isotope is introduced into a compound providedherein by synthetic techniques that employ suitable isotopicallyenriched reagents, whereby isotopic enrichment is pre-determined. Inanother embodiment, an isotope is introduced into a compound providedherein by exchange techniques, wherein isotopic enrichment is determinedby equilibrium conditions, which may be highly variable depending on thereaction conditions. In yet another embodiment, deuterium is introducedinto a compound provided herein by direct deuteration.

In one embodiment, to introduce deuterium at R³, compound S2 with thecorresponding deuterium substitutions is condensed with compound S1 toform deuterated compound S3 with release of hydrobromide and water. Inanother embodiment, to introduce deuterium at one or more positions orgroups of R⁴ and R⁵, compound S1 with the corresponding deuteriumsubstitutions is condensed with compound S2 to form deuterated compoundS3. In yet another embodiment, to introduce deuterium at one or morepositions or groups of R⁶ and R⁷, compound S4 with the correspondingdeuterium is condensed with compound S3 to form deuterated compound S5.The deuterated starting materials and intermediates used herein areeither commercially available, or can be prepared by methods known toone of skill in the art or following procedures similar to thosedescribed herein in the Example section and routine modificationsthereof.

In certain embodiments, deuterium is also incorporated to variouspositions of a compound of Formula I, which has an exchangeable proton,such as amine or amide N—H and hydroxyl O—H, via proton-deuteriumequilibrium exchange.

Pharmaceutical Compositions

In one embodiment, provided herein are pharmaceutical compositionscomprising a compound provided herein, e.g., a compound of Formula I, asan active ingredient, including an enantiomer, a mixture of enantiomers,a mixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or isotopic variants thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; in combinationwith a pharmaceutically acceptable vehicle, carrier, diluent, excipient,or a mixture thereof.

The compound provided herein may be administered alone, or incombination with one or more other compounds provided herein. Thepharmaceutical compositions that comprise a compound provided herein,e.g., a compound of Formula I, can be formulated in various dosage formsfor oral, parenteral, and topical administration. The pharmaceuticalcompositions can also be formulated as modified release dosage forms,including delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated-, fast-, targeted-, programmed-release, andgastric retention dosage forms. These dosage forms can be preparedaccording to conventional methods and techniques known to those skilledin the art (see, Remington: The Science and Practice of Pharmacy, supra;Modified-Release Drug Delivery Technology, 2nd Edition, Rathbone et al.,Eds., Marcel Dekker, Inc.: New York, N.Y., 2008).

In one embodiment, the pharmaceutical compositions provided herein areformulated in a dosage form for oral administration, which comprise acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients or carriers.

In one embodiment, the pharmaceutical compositions provided herein areformulated as a suspension for oral administration, which comprise acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients or carriers. In one embodiment, the suspensionprovided herein comprises a compound provided herein, e.g., a compoundof Formula I, including an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or isotopic variants thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and one or moreexcipients or carriers selected from the group consisting of water,glycerin, sorbitol, sodium saccharin, xanthan gum, flavoring, citricacid, sodium citrate, methylparaben, propylparaben, and potassiumsorbate. In another embodiment, the suspension provided herein comprisesa compound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and water, glycerin, sorbitol,sodium saccharin, xanthan gum, flavoring, citric acid, sodium citrate,methylparaben, propylparaben, and potassium sorbate.

In another embodiment, the pharmaceutical compositions provided hereinare formulated in a dosage form for parenteral administration, whichcomprise a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients or carriers. In one embodiment, the pharmaceuticalcompositions provided herein are formulated in a dosage form forintravenous administration. In another embodiment, the pharmaceuticalcompositions provided herein are formulated in a dosage form forintramuscular administration. In yet another embodiment, thepharmaceutical compositions provided herein are formulated in a dosageform for subcutaneous administration.

In yet another embodiment, the pharmaceutical compositions providedherein are formulated in a dosage form for topical administration, whichcomprise a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients or carriers.

In one embodiment, the pharmaceutical compositions provided herein areformulated as a cream for topical administration, which comprise acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients or carriers. In one embodiment, the cream providedherein comprises a compound provided herein, e.g., a compound of FormulaI, including an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, a tautomer, a mixture of two or more tautomers,or isotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more excipients orcarriers selected from the group consisting of water, octyldodecanol,mineral oil, stearyl alcohol, cocamide DEA, polysorbate 60, myristylalcohol, sorbitan monostearate, lactic acid, and benzyl alcohol. Inanother embodiment, the cream provided herein comprises a compoundprovided herein, e.g., a compound of Formula I, including an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or isotopic variantsthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof; and water, octyldodecanol, mineral oil, stearylalcohol, cocamide DEA, polysorbate 60, myristyl alcohol, sorbitanmonostearate, lactic acid, and benzyl alcohol.

In another embodiment, the pharmaceutical compositions provided hereinare formulated as a gel for topical administration, which comprise acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients or carriers. In one embodiment, the gel providedherein comprises a compound provided herein, e.g., a compound of FormulaI, including an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, a tautomer, a mixture of two or more tautomers,or isotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more excipients orcarriers selected from the group consisting of water, isopropyl alcohol,octyldodecanol, dimethicone copolyol 190, carbomer 980, sodiumhydroxide, and docusate sodium. In another embodiment, the gel providedherein comprises a compound provided herein, e.g., a compound of FormulaI, including an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, a tautomer, a mixture of two or more tautomers,or isotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and water, isopropyl alcohol,octyldodecanol, dimethicone copolyol 190, carbomer 980, sodiumhydroxide, and docusate sodium.

In yet another embodiment, the pharmaceutical compositions providedherein are formulated as a shampoo for topical administration, whichcomprise a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and one or more pharmaceuticallyacceptable excipients or carriers. In one embodiment, the shampooprovided herein comprises a compound provided herein, e.g., a compoundof Formula I, including an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or isotopic variants thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; and one or moreexcipients or carriers selected from the group consisting of water,sodium laureth sulfate, disodium laureth sulfosuccinate, sodiumchloride, and laureth-2. In another embodiment, the shampoo providedherein comprises a compound provided herein, e.g., a compound of FormulaI, including an enantiomer, a mixture of enantiomers, a mixture of twoor more diastereomers, a tautomer, a mixture of two or more tautomers,or isotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof; and water, sodium laureth sulfate,disodium laureth sulfosuccinate, sodium chloride, and laureth-2.

In yet another embodiment, the pharmaceutical compositions providedherein are formulated as a lacquer for topical administration, whichcomprise a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, orisotopic variants thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof and one or more pharmaceuticallyacceptable excipients or carriers. In one embodiment, the lacquerprovided herein comprises a compound provided herein, e.g., a compoundof Formula I, including an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or isotopic variants thereof or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof and one or moreexcipients or carriers selected from the group consisting of ethylacetate, isopropyl alcohol, and butyl monoester of poly(methylvinylether/maleic acid) in isopropyl alcohol. In another embodiment, thelacquer provided herein comprises a compound provided herein, e.g., acompound of Formula I, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or isotopic variants thereof or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereofand ethyl acetate, isopropyl alcohol, and butyl monoester ofpoly(methylvinyl ether/maleic acid) in isopropyl alcohol.

The pharmaceutical compositions provided herein can be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to physically discrete a unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of an activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet and capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein can be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein for oral administrationcan be provided in solid, semisolid, or liquid dosage forms for oraladministration. As used herein, oral administration also includesbuccal, lingual, and sublingual administration. Suitable oral dosageforms include, but are not limited to, tablets, fastmelts, chewabletablets, capsules, pills, strips, troches, lozenges, pastilles, cachets,pellets, medicated chewing gum, bulk powders, effervescent ornon-effervescent powders or granules, oral mists, solutions, emulsions,suspensions, wafers, sprinkles, elixirs, and syrups. In addition to theactive ingredient(s), the pharmaceutical compositions can contain one ormore pharmaceutically acceptable carriers or excipients, including, butnot limited to, binders, fillers, diluents, disintegrants, wettingagents, lubricants, glidants, coloring agents, dye-migration inhibitors,sweetening agents, flavoring agents, emulsifying agents, suspending anddispersing agents, preservatives, solvents, non-aqueous liquids, organicacids, and sources of carbon dioxide.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The amount of a binder or filler in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The binder or filler may be present from about 50 to about 99%by weight in the pharmaceutical compositions provided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets. Theamount of a diluent in the pharmaceutical compositions provided hereinvaries upon the type of formulation, and is readily discernible to thoseof ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The amount of a disintegrant in the pharmaceutical compositionsprovided herein varies upon the type of formulation, and is readilydiscernible to those of ordinary skill in the art. The pharmaceuticalcompositions provided herein may contain from about 0.5 to about 15% orfrom about 1 to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include, but are not limited to, colloidal silicondioxide, CAB-O-SIL® (Cabot Co. of Boston, Mass.), and asbestos-freetalc. Suitable coloring agents include, but are not limited to, any ofthe approved, certified, water soluble FD&C dyes, and water insolubleFD&C dyes suspended on alumina hydrate, and color lakes and mixturesthereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Suitable flavoring agents include, but arenot limited to, natural flavors extracted from plants, such as fruits,and synthetic blends of compounds which produce a pleasant tastesensation, such as peppermint and methyl salicylate. Suitable sweeteningagents include, but are not limited to, sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include, but are not limited to,gelatin, acacia, tragacanth, bentonite, and surfactants, such aspolyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylenesorbitan monooleate 80 (TWEEN® 80), and triethanolamine oleate. Suitablesuspending and dispersing agents include, but are not limited to, sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodiumcarbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Suitable preservatives include, but are notlimited to, glycerin, methyl and propylparaben, benzoic add, sodiumbenzoate and alcohol. Suitable wetting agents include, but are notlimited to, propylene glycol monostearate, sorbitan monooleate,diethylene glycol monolaurate, and polyoxyethylene lauryl ether.Suitable solvents include, but are not limited to, glycerin, sorbitol,ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized inemulsions include, but are not limited to, mineral oil and cottonseedoil. Suitable organic acids include, but are not limited to, citric andtartaric acid. Suitable sources of carbon dioxide include, but are notlimited to, sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein for oral administrationcan be provided as compressed tablets, tablet triturates, chewablelozenges, rapidly dissolving tablets, multiple compressed tablets, orenteric-coating tablets, sugar-coated, or film-coated tablets.Enteric-coated tablets are compressed tablets coated with substancesthat resist the action of stomach acid but dissolve or disintegrate inthe intestine, thus protecting the active ingredients from the acidicenvironment of the stomach. Enteric-coatings include, but are notlimited to, fatty acids, fats, phenyl salicylate, waxes, shellac,ammoniated shellac, and cellulose acetate phthalates. Sugar-coatedtablets are compressed tablets surrounded by a sugar coating, which maybe beneficial in covering up objectionable tastes or odors and inprotecting the tablets from oxidation. Film-coated tablets arecompressed tablets that are covered with a thin layer or film of awater-soluble material. Film coatings include, but are not limited to,hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000, and cellulose acetate phthalate. Film coating imparts thesame general characteristics as sugar coating. Multiple compressedtablets are compressed tablets made by more than one compression cycle,including layered tablets, and press-coated or dry-coated tablets.

The tablet dosage forms can be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administrationcan be provided as soft or hard capsules, which can be made fromgelatin, methylcellulose, starch, or calcium alginate. The hard gelatincapsule, also known as the dry-filled capsule (DFC), consists of twosections, one slipping over the other, thus completely enclosing theactive ingredient. The soft elastic capsule (SEC) is a soft, globularshell, such as a gelatin shell, which is plasticized by the addition ofglycerin, sorbitol, or a similar polyol. The soft gelatin shells maycontain a preservative to prevent the growth of microorganisms. Suitablepreservatives are those as described herein, including methyl- andpropyl-parabens, and sorbic acid. The liquid, semisolid, and soliddosage forms provided herein may be encapsulated in a capsule. Suitableliquid and semisolid dosage forms include solutions and suspensions inpropylene carbonate, vegetable oils, or triglycerides. Capsulescontaining such solutions can be prepared as described in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administrationcan be provided in liquid and semisolid dosage forms, includingemulsions, solutions, suspensions, elixirs, and syrups. An emulsion is atwo-phase system, in which one liquid is dispersed in the form of smallglobules throughout another liquid, which can be oil-in-water orwater-in-oil. Emulsions may include a pharmaceutically acceptablenon-aqueous liquid or solvent, emulsifying agent, and preservative.Suspensions may include a pharmaceutically acceptable suspending agentand preservative. Aqueous alcoholic solutions may include apharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of alower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and awater-miscible solvent having one or more hydroxyl groups, such aspropylene glycol and ethanol. Elixirs are clear, sweetened, andhydroalcoholic solutions. Syrups are concentrated aqueous solutions of asugar, for example, sucrose, and may also contain a preservative. For aliquid dosage form, for example, a solution in a polyethylene glycol maybe diluted with a sufficient quantity of a pharmaceutically acceptableliquid carrier, e.g., water, to be measured conveniently foradministration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations can further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationcan be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein for oral administrationcan be provided as non-effervescent or effervescent, granules andpowders, to be reconstituted into a liquid dosage form. Pharmaceuticallyacceptable carriers and excipients used in the non-effervescent granulesor powders may include diluents, sweeteners, and wetting agents.Pharmaceutically acceptable carriers and excipients used in theeffervescent granules or powders may include organic acids and a sourceof carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein for oral administrationcan be formulated as immediate or modified release dosage forms,including delayed-, sustained, pulsed-, controlled, targeted-, andprogrammed-release forms.

B. Parenteral Administration

The pharmaceutical compositions provided herein can be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated in any dosage forms that are suitablefor parenteral administration, including solutions, suspensions,emulsions, micelles, liposomes, microspheres, nanosystems, and solidforms suitable for solutions or suspensions in liquid prior toinjection. Such dosage forms can be prepared according to conventionalmethods known to those skilled in the art of pharmaceutical science(see, Remington: The Science and Practice of Pharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationcan include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Suitable non-aqueous vehicles include, but are not limited to, fixedoils of vegetable origin, castor oil, corn oil, cottonseed oil, oliveoil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Suitable water-misciblevehicles include, but are not limited to, ethanol, 1,3-butanediol,liquid polyethylene glycol (e.g., polyethylene glycol 300 andpolyethylene glycol 400), propylene glycol, glycerin,N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsare those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

When the pharmaceutical compositions provided herein are formulated formultiple dosage administration, the multiple dosage parenteralformulations must contain an antimicrobial agent at bacteriostatic orfungistatic concentrations. All parenteral formulations must be sterile,as known and practiced in the art.

In one embodiment, the pharmaceutical compositions for parenteraladministration are provided as ready-to-use sterile solutions. Inanother embodiment, the pharmaceutical compositions are provided assterile dry soluble products, including lyophilized powders andhypodermic tablets, to be reconstituted with a vehicle prior to use. Inyet another embodiment, the pharmaceutical compositions are provided asready-to-use sterile suspensions. In yet another embodiment, thepharmaceutical compositions are provided as sterile dry insolubleproducts to be reconstituted with a vehicle prior to use. In stillanother embodiment, the pharmaceutical compositions are provided asready-to-use sterile emulsions.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as immediate or modified release dosageforms, including delayed-, sustained, pulsed-, controlled, targeted-,and programmed-release forms.

The pharmaceutical compositions provided herein for parenteraladministration can be formulated as a suspension, solid, semi-solid, orthixotropic liquid, for administration as an implanted depot. In oneembodiment, the pharmaceutical compositions provided herein aredispersed in a solid inner matrix, which is surrounded by an outerpolymeric membrane that is insoluble in body fluids but allows theactive ingredient in the pharmaceutical compositions diffuse through.

Suitable inner matrixes include, but are not limited to,polymethylmethacrylate, polybutyl-methacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethylene terephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers, such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinyl alcohol, andcross-linked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include but are not limited to,polyethylene, polypropylene, ethylene/propylene copolymers,ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers,silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinatedpolyethylene, polyvinylchloride, vinyl chloride copolymers with vinylacetate, vinylidene chloride, ethylene and propylene, ionomerpolyethylene terephthalate, butyl rubber epichlorohydrin rubbers,ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcoholterpolymer, and ethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein can be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein can be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, and dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereincan also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions can also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein can be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Suitable creamvehicles may be water-washable, and contain an oil phase, an emulsifier,and an aqueous phase. The oil phase is also called the “internal” phase,which is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol. The aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation may be a nonionic,anionic, cationic, or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include, but are not limitedto, crosslinked acrylic acid polymers, such as carbomers,carboxypolyalkylenes, and CARBOPOL®; hydrophilic polymers, such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, andpolyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums, such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

The pharmaceutical compositions provided herein can be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, and polyacrylic acid. Combinations of the various vehiclescan also be used. Rectal and vaginal suppositories may be prepared bycompressing or molding. The typical weight of a rectal and vaginalsuppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein can be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein can be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions can be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions canalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder can comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer can be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein; a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein can be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes can beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters, and cartridges for use in an inhaler or insufflatorcan be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include, but are notlimited to, dextran, glucose, maltose, sorbitol, xylitol, fructose,sucrose, and trehalose. The pharmaceutical compositions provided hereinfor inhaled/intranasal administration can further comprise a suitableflavor, such as menthol and levomenthol; and/or sweeteners, such assaccharin and saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration can be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein can be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include, but are not limited to, delayed-, extended-, prolonged-,sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In certain embodiments, the pharmaceutical compositions provided hereinin a modified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including, but not limited to, synthetic polymers, and naturallyoccurring polymers and derivatives, such as polysaccharides andproteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);polyvinyl pyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerolfatty acid esters; polyacrylamide; polyacrylic acid; copolymers ofethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc.,Piscataway, N.J.); poly(2-hydroxyethyl-methacrylate); polylactides;copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lacticacid-glycolic acid copolymers; poly-D-(−)-3-hydroxybutyric acid; andother acrylic acid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methyl methacrylate, ethyl methacrylate,ethylacrylate, (2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated with a non-erodible matrix device. The activeingredient(s) is dissolved or dispersed in an inert matrix and isreleased primarily by diffusion through the inert matrix onceadministered. Materials suitable for use as a non-erodible matrix deviceinclude, but are not limited to, insoluble plastics, such aspolyethylene, polypropylene, polyisoprene, polyisobutylene,polybutadiene, polymethylmethacrylate, polybutylmethacrylate,chlorinated polyethylene, polyvinylchloride, methyl acrylate-methylmethacrylate copolymers, ethylene-vinyl acetate copolymers,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethyleneand propylene, ionomer polyethylene terephthalate, butyl rubbers,epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer,ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, and silicone carbonate copolymers;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form can be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, and melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated using an osmotic controlled releasedevice, including, but not limited to, one-chamber system, two-chambersystem, asymmetric membrane technology (AMT), and extruding core system(ECS). In general, such devices have at least two components: (a) a corewhich contains an active ingredient; and (b) a semipermeable membranewith at least one delivery port, which encapsulates the core. Thesemipermeable membrane controls the influx of water to the core from anaqueous environment of use so as to cause drug release by extrusionthrough the delivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents is water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels.”Suitable water-swellable hydrophilic polymers as osmotic agents include,but are not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates can be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core can also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking Examples ofsuitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane can also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane can be formedpost-coating by mechanical or laser drilling. Delivery port(s) can alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports can be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform can further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form can be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates can be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein can be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles can themselves constitute themultiparticulate device or can be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein can also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, those disclosed in U.S. Pat. Nos. 6,316,652;6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751;6,071,495; 6,060,082; 6,048,736; 6,039,975; 6,004,534; 5,985,307;5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided herein is a method for treating aproliferative disease in a subject, which comprises administering to thesubject a therapeutically effective amount of a compound providedherein, e.g., a compound of Formula I, including an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

In certain embodiments, the therapeutically effective amount is rangingfrom about 0.1 to about 100 mg/kg/day, from about 0.1 to about 50mg/kg/day, from about 0.1 to about 40 mg/kg/day, from about 0.1 to about30 mg/kg/day, from about 0.1 to about 25 mg/kg/day, from about 0.1 toabout 20 mg/kg/day, from about 0.1 to about 15 mg/kg/day, from about 0.1to about 10 mg/kg/day, or from about 0.1 to about 5 mg/kg/day. In oneembodiment, the therapeutically effective amount is ranging from about0.1 to about 100 mg/kg/day. In another embodiment, the therapeuticallyeffective amount is ranging from about 0.1 to about 50 mg/kg/day. In yetanother embodiment, the therapeutically effective amount is ranging fromabout 0.1 to about 40 mg/kg/day. In yet another embodiment, thetherapeutically effective amount is ranging from about 0.1 to about 30mg/kg/day. In yet another embodiment, the therapeutically effectiveamount is ranging from about 0.1 to about 25 mg/kg/day. In yet anotherembodiment, the therapeutically effective amount is ranging from about0.1 to about 20 mg/kg/day. In yet another embodiment, thetherapeutically effective amount is ranging from about 0.1 to about 15mg/kg/day. In yet another embodiment, the therapeutically effectiveamount is ranging from about 0.1 to about 10 mg/kg/day. In still anotherembodiment, the therapeutically effective amount is ranging from about0.1 to about 5 mg/kg/day.

It is understood that the administered dose can also be expressed inunits other than mg/kg/day. For example, doses for parenteraladministration can be expressed as mg/m²/day. One of ordinary skill inthe art would readily know how to convert doses from mg/kg/day tomg/m²/day to given either the height or weight of a subject or both(see, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1mg/m²/day for a 65 kg human is approximately equal to 38 mg/kg/day.

In certain embodiments, the subject is a mammal. In certain embodiments,the subject is a human.

In certain embodiments, the proliferative disease is a carcinoma,including, but not limited to, Kit-mediated carcinomas, adenocarcinoma,squamous cell carcinoma, adenosquamous carcinoma, teratocarcinoma, headand neck cancer, brain cancer, intracranial carcinoma, glioblastoma(including PDGFR-mediated glioblastoma), glioblastoma multiforme(including PDGFR-mediated glioblastoma multiforme), neuroblastoma,cancer of the larynx, multiple endocrine neoplasias 2A and 2B (MENS 2Aand MENS 2B) (including RET-mediated MENS), thyroid cancer (includingsporadic and familial medullary thyroid carcinoma), papillary thyroidcarcinoma, parathyroid carcinoma (including any RET-mediated thyroidcarcinoma), follicular thyroid cancer, anaplastic thyroid cancer,bronchial carcinoid, oat cell carcinoma, lung cancer, small-cell lungcancer (including FLT3 and/or Kit-mediated small cell lung cancer),stomach/gastric cancer, gastrointestinal cancer, gastrointestinalstromal tumors (GIST) (including Kit-mediated GIST and PDGFR α-mediatedGIST), colon cancer, colorectal cancer, pancreatic cancer, islet cellcarcinoma, hepatic/liver cancer, metastases to the liver, bladdercancer, renal cell cancer (including PDGFR-mediated renal cell cancer),cancers of the genitourinary tract, ovarian cancer (includingKit-mediated and/or PDGFR-mediated ovarian cancer), endometrial cancer(including CSF-1R-mediated endometrial cancer), cervical cancer, breastcancer (including FLT3-mediated and/or PDGFR-mediated breast cancer),prostate cancer (including Kit-mediated prostate cancer), germ celltumors (including Kit-mediated germ cell tumors), seminomas (includingKit-mediated seminomas), dysgerminomas (including Kit-mediateddysgerminomas), melanoma (including PDGFR-mediated melanoma), metastasesto the bone (including CSF-1R-mediated bone metastases), metastatictumors (including VEGFR-mediated tumors), stromal tumors, neuroendocrinetumors, tumor angiogenesis (including VEGFR-mediated tumorangiogenesis), and mixed mesodermal tumors.

In certain embodiments, the proliferative disease is sarcomas,including, but not limited to, PDGFR-mediated sarcomas, osteosarcoma,osteogenic sarcoma, bone cancer, glioma (including PDGFR-mediated and/orCSF-1R-mediated glioma), astrocytoma, vascular tumors (includingVEGFR-mediated vascular tumors), Kaposi's sarcoma, carcinosarcoma,hemangiosarcomas (including VEGFR3-mediated hemangiosarcomas), andlymphangiosarcoma (including VEGFR3-mediated lymphangiosarcoma).

In certain embodiments, the proliferative disease is a hematologicmalignancy. In certain embodiments, the proliferative disease is arelapsed hematologic malignancy. In certain embodiments, theproliferative disease is a refractory hematologic malignancy. In certainembodiments, the proliferative disease is a drug-resistant hematologicmalignancy. In certain embodiments, the proliferative disease is amultidrug-resistant hematologic malignancy. In certain embodiments, theproliferative disease is a Bcr-Abl kinase inhibitor-resistanthematologic malignancy. In certain embodiments, the proliferativedisease is an imatinib-resistant hematologic malignancy. In certainembodiments, the proliferative disease is a dasatinib-resistanthematologic malignancy. In certain embodiments, the proliferativedisease is a nilatinib-resistant hematologic malignancy. In certainembodiments, the proliferative disease is a bosutinib-resistanthematologic malignancy. In certain embodiments, the proliferativedisease is a cytarabine-resistant hematologic malignancy.

In certain embodiments, the hematologic malignancy is myeloma, leukemia,myeloproliferative diseases, acute myeloid leukemia (AML) (includingFLT3 mediated and/or KIT-mediated and/or CSF1R-mediated acute myeloidleukemia), chronic myeloid leukemias (CML) (including FLT3-mediatedand/or PDGFR-mediated chronic myeloid leukemia), myelodysplasticleukemias (including FLT3-mediated myelodysplastic leukemia),myelodysplastic syndrome (including FLT3 mediated and/or Kit-mediatedmyelodysplastic syndrome), idiopathic hypereosinophilic syndrome (HES)(including PDGFR-mediated HES), chronic eosinophilic leukemia (CEL)(including PDGFR-mediated CEL), chronic myelomonocytic leukemia (CMML),mast cell leukemia (including Kit-mediated mast cell leukemia), orsystemic mastocytosis (including Kit-mediated systemic mastocytosis).

In certain embodiments, the hematologic malignancy is lymphoma,lymphoproliferative diseases, acute lymphoblastic leukemia (ALL), B-cellacute lymphoblastic leukemias, T-cell acute lymphoblastic leukemias,chronic lymphocytic leukemia (CLL), natural killer (NK) cell leukemia,B-cell lymphoma, T-cell lymphoma, or natural killer (NK) cell lymphoma.

In certain embodiments, the hematologic malignancy is Langerhans cellhistiocytosis (including CSF-1R-mediated and/or FLT3-mediated Langerhanscell histiocytosis), mast cell tumors, or mastocytosis.

In certain embodiments, the hematologic malignancy is leukemia. Incertain embodiments, the hematologic malignancy is relapsed leukemia. Incertain embodiments, the hematologic malignancy is refractory leukemia.In certain embodiments, the hematologic malignancy is drug-resistantleukemia. In certain embodiments, the hematologic malignancy ismultidrug-resistant leukemia. In certain embodiments, the hematologicmalignancy is a Bcr-Abl kinase inhibitor-resistant leukemia. In certainembodiments, the hematologic malignancy is imatinib-resistant leukemia.In certain embodiments, the hematologic malignancy isdasatinib-resistant leukemia. In certain embodiments, the hematologicmalignancy is nilatinib-resistant leukemia. In certain embodiments, thehematologic malignancy is bosutinib-resistant leukemia. In certainembodiments, the hematologic malignancy is cytarabine-resistantleukemia.

In certain embodiments, the leukemia is acute leukemia. In certainembodiments, the leukemia is relapsed acute leukemia. In certainembodiments, the leukemia is refractory acute leukemia. In certainembodiments, the leukemia is drug-resistant acute leukemia. In certainembodiments, the leukemia is multidrug-resistant acute leukemia. Incertain embodiments, the leukemia is a Bcr-Abl kinaseinhibitor-resistant acute leukemia. In certain embodiments, the leukemiais imatinib-resistant acute leukemia. In certain embodiments, theleukemia is dasatinib-resistant acute leukemia. In certain embodiments,the leukemia is nilatinib-resistant acute leukemia. In certainembodiments, the leukemia is bosutinib-resistant acute leukemia. Incertain embodiments, the leukemia is cytarabine-resistant acuteleukemia. In certain embodiments, the leukemia is a hereditary leukemia.In certain embodiments, the hereditary leukemia is severe congenitalneutropenia (SCN). In certain embodiments, the hereditary leukemia isfamilial platelet disorder with acute myelogenous leukemia (FDP/AML). Incertain embodiments, the leukemia is caused by LEF1. In certainembodiments, the leukemia is mediated by LEF1. In certain embodiments,the leukemia is caused by GSK3.

In certain embodiments, the leukemia is ALL. In certain embodiments, theleukemia is relapsed ALL. In certain embodiments, the leukemia isrefractory ALL. In certain embodiments, the leukemia is drug-resistantALL. In certain embodiments, the leukemia is multidrug-resistant ALL. Incertain embodiments, the leukemia is a Bcr-Abl kinaseinhibitor-resistant ALL. In certain embodiments, the leukemia isimatinib-resistant ALL. In certain embodiments, the leukemia isdasatinib-resistant ALL. In certain embodiments, the leukemia isnilatinib-resistant ALL. In certain embodiments, the leukemia isbosutinib-resistant ALL. In certain embodiments, the leukemia iscytarabine-resistant ALL.

In one embodiment, ALL is leukemia that originates in the blast cells ofthe bone marrow (B-cells), thymus (T-cells), or lymph nodes. ALL iscategorized according to the French-American-British (FAB) MorphologicalClassification Scheme as L1-mature-appearing lymphoblasts (T-cells orpre-B-cells), L2-immature and pleomorphic (variously shaped)lymphoblasts (T-cells or pre-B-cells), and L3-lymphoblasts (B-cells;Burkitt's cells). In another embodiment, ALL originates in the blastcells of the bone marrow (B-cells). In yet another embodiment, ALLoriginates in the thymus (T-cells). In yet another embodiment, ALLoriginates in the lymph nodes. In yet another embodiment, ALL is L1 typecharacterized by mature-appearing lymphoblasts (T-cells or pre-B-cells).In yet another embodiment, ALL is L2 type characterized by immature andpleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). Instill another embodiment, ALL is L3 type characterized by lymphoblasts(B-cells; Burkitt's cells).

In certain embodiments, the leukemia is AML. In certain embodiments, theleukemia is relapsed AML. In certain embodiments, the leukemia isrefractory AML. In certain embodiments, the leukemia is drug-resistantAML. In certain embodiments, the leukemia is multidrug-resistant AML. Incertain embodiments, the leukemia is a Bcr-Abl kinaseinhibitor-resistant AML. In certain embodiments, the leukemia isimatinib-resistant AML. In certain embodiments, the leukemia isdasatinib-resistant AML. In certain embodiments, the leukemia isnilatinib-resistant AML. In certain embodiments, the leukemia isbosutinib-resistant AML. In certain embodiments, the leukemia iscytarabine-resistant AML. In certain embodiments, AML has a RASmutation. In certain embodiments, the RAS mutation is NRAS, KRAS, orHRAS. In certain embodiments, the RAS mutation is NRAS. In certainembodiments, the RAS mutation is KRAS. In certain embodiments, the RASmutation is HRAS.

In certain embodiments, AML is undifferentiated AML (M0), myeloblasticleukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 orM3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant witheosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), ormegakaryoblastic leukemia (M7). In one embodiment, AML isundifferentiated AML (M0). In another embodiment, AML is myeloblasticleukemia (Ml). In yet another embodiment, AML is myeloblastic leukemia(M2). In yet another embodiment, AML is promyelocytic leukemia (M3 or M3variant [M3V]). In yet another embodiment, AML is myelomonocyticleukemia (M4 or M4 variant with eosinophilia [M4E]). In yet anotherembodiment, AML is monocytic leukemia (M5). In yet another embodiment,AML is erythroleukemia (M6). In still another embodiment, AML ismegakaryoblastic leukemia (M7).

In certain embodiments, the leukemia is chronic leukemia. In certainembodiments, the leukemia is relapsed chronic leukemia. In certainembodiments, the leukemia is refractory chronic leukemia. In certainembodiments, the leukemia is drug-resistant chronic leukemia. In certainembodiments, the leukemia is multidrug-resistant chronic leukemia. Incertain embodiments, the leukemia is a Bcr-Abl kinaseinhibitor-resistant chronic leukemia. In certain embodiments, theleukemia is imatinib-resistant chronic leukemia. In certain embodiments,the leukemia is dasatinib-resistant chronic leukemia. In certainembodiments, the leukemia is nilatinib-resistant chronic leukemia. Incertain embodiments, the leukemia is bosutinib-resistant chronicleukemia. In certain embodiments, the leukemia is cytarabine-resistantchronic leukemia.

In certain embodiments, the leukemia is CLL. In certain embodiments, theleukemia is relapsed CLL. In certain embodiments, the leukemia isrefractory CLL. In certain embodiments, the leukemia is drug-resistantCLL. In certain embodiments, the leukemia is multidrug-resistant CLL. Incertain embodiments, the leukemia is a Bcr-Abl kinaseinhibitor-resistant CLL. In certain embodiments, the leukemia isimatinib-resistant CLL. In certain embodiments, the leukemia isdasatinib-resistant CLL. In certain embodiments, the leukemia isnilatinib-resistant CLL. In certain embodiments, the leukemia isbosutinib-resistant CLL. In certain embodiments, the leukemia iscytarabine-resistant CLL.

In certain embodiments, the leukemia is CML. In certain embodiments, theleukemia is relapsed CML. In certain embodiments, the leukemia isrefractory CML. In certain embodiments, the leukemia is drug-resistantCML. In certain embodiments, the leukemia is multidrug-resistant CML. Incertain embodiments, the leukemia is a Bcr-Abl kinaseinhibitor-resistant CML. In certain embodiments, the leukemia isimatinib-resistant CML. In certain embodiments, the leukemia isdasatinib-resistant CML. In certain embodiments, the leukemia isnilatinib-resistant CML. In certain embodiments, the leukemia isbosutinib-resistant CML. In certain embodiments, the leukemia iscytarabine-resistant CML. In certain embodiments, the leukemia isjuvenile CML. In certain embodiments, the leukemia is juvenile CML withone or more NF-1 mutations.

In certain embodiments, the leukemia is T-cell leukemia. In oneembodiment, the T-cell leukemia is peripheral T-cell leukemia, T-celllymphoblastic leukemia, cutaneous T-cell leukemia, and adult T-cellleukemia. In another embodiment, the T-cell leukemia is peripheralT-cell leukemia. In yet another embodiment, the T-cell leukemia isT-cell lymphoblastic leukemia. In yet another embodiment, the T-cellleukemia is cutaneous T-cell leukemia. In still another embodiment, theT-cell leukemia is adult T-cell leukemia.

In certain embodiments, the leukemia is Philadelphia positive. In oneembodiment, the Philadelphia positive leukemia is Philadelphia positiveAML, including, but not limited to, undifferentiated AML (MO),myeloblastic leukemia (Ml), myeloblastic leukemia (M2), promyelocyticleukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4variant with eosinophilia [M4E]), monocytic leukemia (M5),erythroleukemia (M6), or megakaryoblastic leukemia (M7). In anotherembodiment, the Philadelphia positive leukemia is Philadelphia positiveALL.

In certain embodiments, the proliferative disease is cancer, including,but not limited to, head and neck cancer (originating lip, oral cavity,oropharynx, hypopharynx, larynx, nasopharynx, nasal cavity, paranasalsinuses, or salivary glands), lung cancer (including small cell lungcancer and non-small cell lung cancer), gastrointestinal tract cancers(including esophageal cancer), gastric cancer, colorectal cancer, analcancer, pancreatic cancer, liver cancer, gallbladder cancer,extrahepatic bile duct cancer, cancer of the ampulla of vater, breastcancer, gynecologic cancers (including cancer of uterine cervix), cancerof the uterine body, vaginal cancer, vulvar cancer, ovarian cancer,gestational trophoblastic cancer neoplasia, testicular cancer, urinarytract cancers (including renal cancer), urinary bladder cancer, prostatecancer, penile cancer, urethral cancer, neurologic tumors, endocrineneoplasms (including carcinoid and islet cell tumors), pheochromocytoma,adrenal cortical carcinoma, parathyroid carcinoma and metastases toendocrine glands.

Further examples of cancers are basal cell carcinoma, squamous cellcarcinoma, chondrosarcoma (a cancer arising in cartilage cells),mesenchymal-chondrosarcoma, soft tissue sarcomas (including malignanttumors that may arise in any of the mesodermal tissues (muscles,tendons, vessels that carry blood or lymph, joints and fat)), softtissue sarcomas (include alveolar soft-part sarcoma), angiosarcoma,fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibroushistiocytoma, hemangiopericytoma, mesenchymoma, schwannoma, peripheralneuroectodermal tumours, rhabdomyosarcoma, synovial sarcoma, gestationaltrophoblastic tumor (malignancy in which the tissues formed in theuterus following conception become cancerous), Hodgkin's lymphoma, andlaryngeal cancer.

In certain embodiments, the proliferative disease is a nonmalignantproliferation disease, including, but not limited to, atherosclerosis(including PDGFR-mediated atherosclerosis), restenosis followingvascular angioplasty (including PDGFR-mediated restenosis), andfibroproliferative disorders (including obliterative bronchiolitis andidiopathic myelofibrosis).

In certain embodiments, the proliferative disease is an inflammatorydisease or disorder related to immune dysfunction, immunodeficiency, orimmunomodulation, including, but not limited to, autoimmune diseases,tissue transplant rejection, graft-versus-host disease, wound healing,kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes,sarcoidosis, allergic rhinitis, inflammatory bowel diseases (includingCrohn's disease and ulcerative colitis (UC)), systemic lupuserythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis,osteoporosis, asthma, and chronic obstructive pulmonary disease (COPD).

In certain embodiments, the proliferative disease is an infectiousdisease. In certain embodiments, the infectious disease is fungalinfection. In certain embodiments, the infectious disease is asuperficial mycose (e.g., Tinea versicolor). In certain embodiments, theinfectious disease is a cutaneous mycose (e.g., epidermis). In certainembodiments, the infectious disease is a subcutaneous mycose. In certainembodiments, the infectious disease is a systemic mycose.

In certain embodiments, the proliferative disease is leukemia, adultT-cell leukemia, promyelocytic leukemia, pre-B cell leukemia, lymphoma,Mantle cell lymphoma, breast cancer, pancreatic cancer, prostate cancer,head and neck cancer, ovarian cancer, melanoma, giloma, liver cancer,renal cancer, colorectal cancer, rhabdomyosarcoma, tongue cancer,stomach cancer, multiple myeloma, bladder cancer, thyroid cancer,epidermoid carcinoma, lung cancer, NSC lung cancer, or large cell lungcancer.

In certain embodiments, the proliferative disease is adult T-cellleukemia, promyelocytic leukemia, pre-B cell leukemia, lymphoma, mantlecell lymphoma, pancreatic cancer, prostate cancer, head and neck cancer,ovarian cancer, melanoma, giloma, liver cancer, renal cancer, colorectalcancer, rhabdomyosarcoma, tongue cancer, stomach cancer, multiplemyeloma, bladder cancer, thyroid cancer, epidermoid carcinoma, NSC lungcancer, or large cell lung cancer.

In certain embodiments, the proliferative disease is leukemia, adultT-cell leukemia, promyelocytic leukemia, pre-B cell leukemia, lymphoma,mantle cell lymphoma, breast cancer, head and neck cancer, ovariancancer, colorectal cancer, tongue cancer, multiple myeloma, or largecell lung cancer.

In certain embodiments, the subject to be treated with one of themethods provided herein has not been treated with anticancer therapy forthe proliferative disease to be treated prior to the administration of acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In certain embodiments, the subject to be treated with one of themethods provided herein has been treated with anticancer therapy for theproliferative disease to be treated prior to the administration of acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof.

In certain embodiments, the subject to be treated with one of themethods provided herein has developed drug resistance to the anticancertherapy.

The methods provided herein encompass treating a subject regardless ofpatient's age, although some diseases or disorders are more common incertain age groups. Further provided herein is a method for treating asubject who has undergone surgery in an attempt to treat the disease orcondition at issue, as well as the one who have not. Because thesubjects with cancer have heterogeneous clinical manifestations andvarying clinical outcomes, the treatment given to a particular subjectmay vary, depending on his/her prognosis. The skilled clinician will beable to readily determine without undue experimentation, specificsecondary agents, types of surgery, and types of non-drug based standardtherapy that can be effectively used to treat an individual subject withcancer.

Depending on the disease to be treated and the subject's condition, acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV,intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration. A compoundprovided herein, e.g., an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, may beformulated, alone or together, in suitable dosage unit withpharmaceutically acceptable excipients, carriers, adjuvants andvehicles, appropriate for each route of administration.

In one embodiment, a compound provided herein, e.g., a compound ofFormula I, including an enantiomer, a mixture of enantiomers, a mixtureof two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, is administeredorally. In another embodiment, a compound provided herein, e.g., acompound of Formula I, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,is administered parenterally. In yet another embodiment, a compoundprovided herein, e.g., a compound of Formula I, including an enantiomer,a mixture of enantiomers, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof, is administered intravenously. In yet anotherembodiment, a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, a mixture of two ormore diastereomers, a tautomer, a mixture of two or more tautomers, oran isotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, is administered intramuscularly.In yet another embodiment, a compound provided herein, e.g., a compoundof Formula I, including an enantiomer, a mixture of enantiomers, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, is administeredsubcutaneously. In still another embodiment, a compound provided herein,e.g., a compound of Formula I, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,is administered topically.

A compound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, can be delivered as a single dosesuch as, e.g., a single bolus injection, or oral tablets or pills; orover time such as, e.g., continuous infusion over time or divided bolusdoses over time. The compound provided herein can be administeredrepetitively if necessary, for example, until the patient experiencesstable disease or regression, or until the patient experiences diseaseprogression or unacceptable toxicity. For example, stable disease forsolid tumors generally means that the perpendicular diameter ofmeasurable lesions has not increased by 25% or more from the lastmeasurement. Response Evaluation Criteria in Solid Tumors (RECIST)Guidelines, Journal of the National Cancer Institute 92(3): 205-216(2000). Stable disease or lack thereof is determined by methods known inthe art such as evaluation of patient symptoms, physical examination,visualization of the tumor that has been imaged using X-ray, CAT, PET,or MRI scan and other commonly accepted evaluation modalities.

A compound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, can be administered once daily(QD), or divided into multiple daily doses such as twice daily (BID),and three times daily (TID). In addition, the administration can becontinuous, i.e., every day, or intermittently. The term “intermittent”or “intermittently” as used herein is intended to mean stopping andstarting at either regular or irregular intervals. For example,intermittent administration of a compound provided herein, e.g., acompound of Formula I, including an enantiomer, a mixture ofenantiomers, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof,is administration for one to six days per week, administration in cycles(e.g., daily administration for two to eight consecutive weeks, then arest period with no administration for up to one week), oradministration on alternate days.

In certain embodiments, a compound provided herein, e.g., a compound ofFormula I, including an enantiomer, a mixture of enantiomers, a mixtureof two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof, is cyclicallyadministered to a patient. Cycling therapy involves the administrationof an active agent for a period of time, followed by a rest for a periodof time, and repeating this sequential administration. Cycling therapycan reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improves the efficacy of the treatment.

A compound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof; or a pharmaceutically acceptable salt,solvate, hydrate, or prodrug thereof, can also be combined or used incombination with other therapeutic agents useful in the treatment and/orprevention of a disease described herein.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein) can be administered prior to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantlywith, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks after) the administration of a secondtherapy (e.g., a prophylactic or therapeutic agent) to the subject.Triple therapy is also contemplated herein.

The route of administration of a compound provided herein, e.g., acompound of Formula I, including an enantiomer, a mixture ofenantiomers, or a mixture of diastereomers thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof, isindependent of the route of administration of a second therapy. In oneembodiment, a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof, is administered orally. In another embodiment, acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, or a mixture of diastereomersthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, is administered intravenously. Thus, in accordance with theseembodiments, a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof, is administered orally or intravenously, and thesecond therapy can be administered orally, parenterally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,liposomally, via inhalation, vaginally, intraoccularly, via localdelivery by catheter or stent, subcutaneously, intraadiposally,intraarticularly, intrathecally, or in a slow release dosage form. Inone embodiment, a compound provided herein, e.g., a compound of FormulaI, including an enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof, and a second therapy are administered by the samemode of administration, orally or by IV. In another embodiment, acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, or a mixture of diastereomersthereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, is administered by one mode of administration, e.g., by IV,whereas the second agent (an anticancer agent) is administered byanother mode of administration, e.g., orally.

In certain embodiments, each method provided herein may independently,further comprise the step of administering a second therapeutic agent.In one embodiment, the second therapeutic agent is an anticancer agent.In another embodiment, the anticancer agent is an antimetabolite,including, but not limited to, 5-fluoro uracil, methotrexate, cytarabine(also known as cytosine arabinoside or Ara-C), and HDAC (high dosecytarabine) and fludarabine. In yet another embodiment, the anticanceragent is an antimicrotubule agent, including, but not limited to, vincaalkaloids (e.g., vincristine and vinblastine) and taxanes (e.g.,paclitaxel and docetaxel). In yet another embodiment, the anticanceragent is an alkylating agent, including, but not limited to,cyclophosphamide, melphalan, carmustine, and nitrosoureas (e.g.,bischloroethylnitrosurea and hydroxyurea). In yet another embodiment,the anticancer agent is a platinum agent, including, but not limited to,cisplatin, carboplatin, oxaliplatin, satraplatin (JM-216), and CI-973.In yet another embodiment, the anticancer agent is an anthracycline,including, but not limited to, doxrubicin and daunorubicin. In yetanother embodiment, the anticancer agent is an antitumor antibiotic,including, but not limited to, mitomycin, idarubicin, adriamycin, anddaunomycin (also known as daunorubicin). In yet another embodiment, theanticancer agent is a topoisomerase inhibitor, e.g., etoposide andcamptothecins. In yet another embodiment, the anticancer agent isselected from the group consisting of adriamycin, busulfan, cytarabine,cyclophosphamide, dexamethasone, fludarabine, fluorouracil, hydroxyurea,interferons, oblimersen, platinum derivatives, taxol, topotecan, andvincristine.

In another embodiment, the anticancer agent is a Bcr-Abl kinaseinhibitor. In one embodiment, the Bcr-Abl kinase inhibitor is selectedfrom the group consisting of imatinib, BMS354825 (dasatinib), AMN107(nilotinib), AP23464, AZD0530, CGP76030, ON012380, INN-0406 (NS-187),SKI-606 (bosutinib), VX-680, and pyrrolo[2,3-d]pyrimidines includingPD166326, PD173955 and PD180970. In another embodiment, the Bcr-Ablkinase inhibitor is imatinib. In yet another embodiment, the Bcr-Ablkinase inhibitor is dasatinib. In yet another embodiment, the Bcr-Ablkinase inhibitor is nilotinib. In yet another embodiment, the Bcr-Ablkinase inhibitor is AP23464. In yet another embodiment, the Bcr-Ablkinase inhibitor is AZD0530. In yet another embodiment, the Bcr-Ablkinase inhibitor is CGP76030. In yet another embodiment, the Bcr-Ablkinase inhibitor is SKI-606. In yet another embodiment, the Bcr-Ablkinase inhibitor is ON012380. In yet another embodiment, the Bcr-Ablkinase inhibitor is INN-0406 (NS-187). In yet another embodiment, theBcr-Abl kinase inhibitor is a pyrrolo[2,3-d]pyrimidine. In anotherembodiment, the Bcr-Abl kinase inhibitor is VX-680. In anotherembodiment, the Bcr-Abl kinase inhibitor is PD166326. In yet anotherembodiment, the Bcr-Abl kinase inhibitor is PD173955. In still anotherembodiment, the Bcr-Abl kinase inhibitor is PD180970.

In still another embodiment, the anticancer agent is a FLT3 kinaseinhibitor. In one embodiment, the FLT3 kinase inhibitor is selected fromthe group consisting of PKC 412, MLN 578, CEP-701, CT 53518, CT-53608,CT-52923, D-64406, D-65476, AGL-2033, AG1295, AG1296, KN-1022, PKC-412,SU5416, SU5614, SU11248, L-00021649, and CHIR-258. In anotherembodiment, the FLT3 kinase inhibitor is PKC 412. In yet anotherembodiment, the FLT3 kinase inhibitor is MLN 578. In yet anotherembodiment, the FLT3 kinase inhibitor is CEP-701. In yet anotherembodiment, the FLT3 kinase inhibitor is CT 53518. In yet anotherembodiment, the FLT3 kinase inhibitor is CT-53608. In yet anotherembodiment, the FLT3 kinase inhibitor is CT-52923. In yet anotherembodiment, the FLT3 kinase inhibitor is D-64406. In yet anotherembodiment, the FLT3 kinase inhibitor is D-65476. In yet anotherembodiment, the FLT3 kinase inhibitor is AGL-2033. In yet anotherembodiment, the FLT3 kinase inhibitor is AG1295. In yet anotherembodiment, the FLT3 kinase inhibitor is AG1296. In yet anotherembodiment, the FLT3 kinase inhibitor is KN-1022. In yet anotherembodiment, the FLT3 kinase inhibitor is KN-1022. In yet anotherembodiment, the FLT3 kinase inhibitor is SU5416. In yet anotherembodiment, the FLT3 kinase inhibitor is SU5614. In yet anotherembodiment, the FLT3 kinase inhibitor is SU11248. In yet anotherembodiment, the FLT3 kinase inhibitor is L-00021649. In still anotherembodiment, the FLT3 kinase inhibitor is CHIR-258.

Other therapies or anticancer agents that may be used in combinationwith a compound provided herein, e.g., a compound of Formula I,including an enantiomer, a mixture of enantiomers, or a mixture ofdiastereomers thereof; or a pharmaceutically acceptable salt, solvate,or prodrug thereof, include surgery, radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes),endocrine therapy, biologic response modifiers (e.g., interferons,interleukins, and tumor necrosis factor (TNF)), hyperthermia andcryotherapy, agents to attenuate any adverse effects (e.g.,antiemetics), and other approved chemotherapeutic drugs, including, butnot limited to, alkylating drugs (mechlorethamine, chlorambucil,cyclophosphamide, melphalan, and ifosfamide), antimetabolites(cytarabine (also known as cytosine arabinoside or Ara-C), HDAC (highdose cytarabine), and methotrexate), purine antagonists and pyrimidineantagonists (6-mercaptopurine, 5-fluorouracil, cytarbine, andgemcitabine), spindle poisons (vinblastine, vincristine, vinorelbine,and paclitaxel), podophyllotoxins (etoposide, irinotecan, andtopotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, andmitomycin), nitrosoureas (carmustine and lomustine), inorganic ions(cisplatin and carboplatin), enzymes (asparaginase), and hormones(tamoxifen, leuprolide, flutamide, and megestrol), imatinib, adriamycin,dexamethasone, and cyclophosphamide. For a more comprehensive discussionof updated cancer therapies see, http://www.nci.nih.gov/, a list of theFDA approved oncology drugs athttp://www.fda.gov/cder/cancer/druglistframe.htm, and The Merck Manual,Seventeenth Ed. 1999, the entire contents of which are herebyincorporated by reference.

The compounds provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

In certain embodiments, provided herein also are kits which, when usedby the medical practitioner, can simplify the administration ofappropriate amounts of active ingredients to a subject. In certainembodiments, the kit provided herein includes a container and a dosageform of a compound provided herein, including a single enantiomer or amixture of diastereomers thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof.

In certain embodiments, the kit includes a container comprising a dosageform of the compound provided herein, including a single enantiomer or amixture of diastereomers thereof or a pharmaceutically acceptable salt,solvate, or prodrug thereof, in a container comprising one or more othertherapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

In certain embodiments, provided herein is a method of inhibiting thegrowth of a cell, comprising the step of contacting the cell with acompound provided herein, e.g., a compound of Formula I, including anenantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, a mixture of two or more tautomers, or anisotopic variant thereof or a pharmaceutically acceptable salt, solvate,hydrate, or prodrug thereof.

In certain embodiment, the effective amount of the compound providedherein ranges from about 1 pM to about 1 mM, from about 10 pM to about10 μM, from about 100 pM to about 2 μM, or from about 1 nM to about 1μM.

In certain embodiments, the cell is a mammalian cell. In certainembodiments, the mammal is a human cell. In certain embodiment, the cellis a tumor cell. In certain embodiment, the cell is a mammalian tumorcell. In certain embodiment, the cell is a human tumor cell. In certainembodiment, the cell is a cancerous cell. In certain embodiment, thecell is a mammalian cancerous cell. In certain embodiment, the cell is ahuman cancerous cell. In certain embodiment, the cancerous cell is ametastatic cancerous cell. In certain embodiment, the cancerous cell isa metastatic microbial cell. In certain embodiment, the cancerous cellis a metastatic bacterial cell. In certain embodiment, the cancerouscell is a metastatic fungal cell.

In certain embodiment, the cell is a hematologic malignancy cell. Incertain embodiment, the cell is a leukemia cell. In certain embodiments,the cell is a relapsed leukemia cell. In certain embodiments, the cellis a refractory leukemia cell. In certain embodiments, the cell is adrug-resistant leukemia cell. In certain embodiments, the cell is amultidrug-resistant leukemia cell. In certain embodiments, the cell is aBcr-Abl kinase inhibitor-resistant leukemia cell. In certainembodiments, the cell is an imatinib-resistant leukemia cell. In certainembodiments, the cell is a dasatinib-resistant leukemia cell. In certainembodiments, the cell is a nilatinib-resistant leukemia cell. In certainembodiments, the cell is a bosutinib-resistant leukemia cell. In certainembodiments, the cell is a cytarabine-resistant leukemia cell.

In certain embodiment, the cell is a leukemia stem cell. In certainembodiments, the cell is a relapsed leukemia stem cell. In certainembodiments, the cell is a refractory leukemia stem cell. In certainembodiments, the cell is a drug-resistant leukemia stem cell. In certainembodiments, the cell is a multidrug-resistant leukemia stem cell. Incertain embodiments, the cell is a Bcr-Abl kinase inhibitor-resistantleukemia stem cell. In certain embodiments, the cell is animatinib-resistant leukemia stem cell. In certain embodiments, the cellis a dasatinib-resistant leukemia stem cell. In certain embodiments, thecell is a nilatinib-resistant leukemia stem cell. In certainembodiments, the cell is a bosutinib-resistant leukemia stem cell. Incertain embodiments, the cell is a cytarabine-resistant leukemia stemcell.

In certain embodiment, the cell is an acute leukemia cell. In certainembodiments, the cell is a relapsed acute leukemia cell. In certainembodiments, the cell is a refractory acute leukemia cell. In certainembodiments, the cell is a drug-resistant acute leukemia cell. Incertain embodiments, the cell is a multidrug-resistant acute leukemiacell. In certain embodiments, the cell is a Bcr-Abl kinaseinhibitor-resistant acute leukemia cell. In certain embodiments, thecell is an imatinib-resistant acute leukemia cell. In certainembodiments, the cell is a dasatinib-resistant acute leukemia cell. Incertain embodiments, the cell is a nilatinib-resistant acute leukemiacell. In certain embodiments, the cell is a bosutinib-resistant acuteleukemia cell. In certain embodiments, the cell is acytarabine-resistant acute leukemia cell.

In certain embodiments, the cell is an ALL cell. In certain embodiments,the cell is a relapsed ALL cell. In certain embodiments, the cell is arefractory ALL cell. In certain embodiments, the cell is adrug-resistant ALL cell. In certain embodiments, the cell is amultidrug-resistant ALL cell. In certain embodiments, the cell is aBcr-Abl kinase inhibitor-resistant ALL cell. In certain embodiments, thecell is an imatinib-resistant ALL cell. In certain embodiments, the cellis a dasatinib-resistant ALL cell. In certain embodiments, the cell is anilatinib-resistant ALL cell. In certain embodiments, the cell is abosutinib-resistant ALL cell. In certain embodiments, the cell is acytarabine-resistant ALL cell.

In certain embodiments, the cell is an AML cell. In certain embodiments,the cell is a relapsed AML cell. In certain embodiments, the cell is arefractory AML cell. In certain embodiments, the cell is adrug-resistant AML cell. In certain embodiments, the cell is amultidrug-resistant AML cell. In certain embodiments, the cell is aBcr-Abl kinase inhibitor-resistant AML cell. In certain embodiments, thecell is an imatinib-resistant AML cell. In certain embodiments, the cellis a dasatinib-resistant AML cell. In certain embodiments, the cell is anilatinib-resistant AML cell. In certain embodiments, the cell is abosutinib-resistant AML cell. In certain embodiments, the cell is acytarabine-resistant AML cell.

In certain embodiment, the cell is a chronic leukemia cell. In certainembodiments, the cell is a relapsed chronic leukemia cell. In certainembodiments, the cell is a refractory chronic leukemia cell. In certainembodiments, the cell is a drug-resistant chronic leukemia cell. Incertain embodiments, the cell is a multidrug-resistant chronic leukemiacell. In certain embodiments, the cell is a Bcr-Abl kinaseinhibitor-resistant chronic leukemia cell. In certain embodiments, thecell is an imatinib-resistant chronic leukemia cell. In certainembodiments, the cell is a dasatinib-resistant chronic leukemia cell. Incertain embodiments, the cell is a nilatinib-resistant chronic leukemiacell. In certain embodiments, the cell is a bosutinib-resistant chronicleukemia cell. In certain embodiments, the cell is acytarabine-resistant chronic leukemia cell.

In certain embodiments, the cell is a CLL cell. In certain embodiments,the cell is a relapsed CLL cell. In certain embodiments, the cell is arefractory CLL cell. In certain embodiments, the cell is adrug-resistant CLL cell. In certain embodiments, the cell is amultidrug-resistant CLL cell. In certain embodiments, the cell is aBcr-Abl kinase inhibitor-resistant CLL cell. In certain embodiments, thecell is an imatinib-resistant CLL cell. In certain embodiments, the cellis a dasatinib-resistant CLL cell. In certain embodiments, the cell is anilatinib-resistant CLL cell. In certain embodiments, the cell is abosutinib-resistant CLL cell. In certain embodiments, the cell is acytarabine-resistant CLL cell.

In certain embodiments, the cell is a CML cell. In certain embodiments,the cell is a relapsed CML cell. In certain embodiments, the cell is arefractory CML cell. In certain embodiments, the cell is adrug-resistant CML cell. In certain embodiments, the cell is amultidrug-resistant CML cell. In certain embodiments, the cell is aBcr-Abl kinase inhibitor-resistant CML cell. In certain embodiments, thecell is an imatinib-resistant CML cell. In certain embodiments, the cellis a dasatinib-resistant CML cell. In certain embodiments, the cell is anilatinib-resistant CML cell. In certain embodiments, the cell is abosutinib-resistant CML cell. In certain embodiments, the cell is acytarabine-resistant CML cell.

In certain embodiments, the cell is Philadelphia positive leukemia cell.In one embodiment, the cell is a Philadelphia positive ALL cell. Inanother embodiment, the cell is a Philadelphia positive AML cell. In yetanother embodiment, the cell is a Philadelphia positive CLL cell. Instill another embodiment, the cell is a Philadelphia positive CML cell.

The inhibition of cell growth can be gauged by, e.g., counting thenumber of cells contacted with a compound of interest, comparing thecell proliferation with otherwise identical cells not contacted with thecompound, or determining the size of the tumor that encompasses thecells. The number of cells, as well as the size of the cells, can bereadily assessed using any method known in the art (e.g., trypan blueexclusion and cell counting, measuring incorporation of ³H-thymidineinto nascent DNA in a cell).

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar); Hz(Hertz); MHz (megahertz); mmol (millimoles); hr or hrs (hours); min(minutes); MS (mass spectrometry); ESI (electrospray ionization); TLC(thin layer chromatography); HPLC (high pressure liquid chromatography);THF (tetrahydrofuran); CDCl₃ (deuterated chloroform); DMSO(dimethylsulfoxide); DMSO-d₆ (deuterated dimethylsulfoxide); EtOAc(ethyl acetate); and MeOH (methanol).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise noted. Synthetic methodologies illustrated herein are intendedto exemplify the applicable chemistry through the use of specificexamples and are not indicative of the scope of the disclosure.

Example 1 General Biological Methods

Cell Culture

Leukemia cells or cell lines (HL-60, RSV411, k562, Jurkat, U937),lymphoma cells or cellines (MDAY-D2), solid tumor cells or cell lines(PPC-1, HeLa, OVCAR-3, DU-145, HT-29), and GM05757 human lungfibroblasts, are cultured in RPMI 1640 medium. HepG2 hepatoma cells andMRC5 human lung fibroblasts are grown in Dulbecco modified Eagle medium.OCI-M2, OCI-AML2, and NB4 leukemia cell lines and OPM2, KMS11, LP1,UTMC2, KSM18, and OCIMy5 myeloma cell lines are maintained in IscoveModified Dulbecco Medium. LF1 human lung fibroblasts are maintained inHAM medium. All media are supplemented with 10% fetal calf serum, 100μg/mL of penicillin, and 100 units/mL of streptomycin (all from Hyclone,Logan, Utah). The cells are incubated at 37° C. in a humidified airatmosphere supplemented with 5% CO₂.

Cell Cycle

Cells are harvested, washed with cold PBS, resuspended in 70% coldethanol, and incubated overnight at −20° C. Cells are then treated with100 ng/mL of DNase-free RNase (Invitrogen, Carlsbad, Calif.) at 37° C.for 30 min, washed with cold PBS, and resuspended in PBS with 50 μg/mLof protease inhibitors (Sigma). DNA content is analyzed by flowcytometry (FACSCalibur; BD Biosciences, San Jose, Calif.).

Example 2 Luciferase Assay for Anti-Cancer Activity

The anticancer activity of a compound is determined using the luciferaseassay as described herein.

For the luciferase assay, HeLa cells that stably over-express the humansurvivin promoter driving firefly luciferase are used, which areprepared by first isolating the full-length survivin promoter (-1059upstream of the initiating ATG) from HeLa genomic DNA using the forwardprimer 5′-GGCGAGCTCACTTTTTCTGTCACCTCCGTGGTCCG-3′ (SEQ ID NO: 1) and thereverse primer 5′-GGGTTCGAAACGGCGGCGGCGGTGGAGA-3′ (SEQ ID NO:2). Thesurvivin promoter is then sub-cloned into the GL4.20 firefly luciferasereporter vector (Promega Corporation, Madison, Wis.). Clones aresequence-verified for orientation and integrity using a CEQ 8000 GeneticAnalysis System (Beckman, Mississauga, ON, Canada). HeLa cells aretransfected with survivin promoter construct alone or vector alone usingLipofectamine (Invitrogen, CA), and selected with Puromycin (4 μg/mL)(Sigma) for stable clones. Stable HeLa cells thus selected are used fortesting the compound for its anticancer activity.

To determine anticancer activity, HeLa cells stably over-expressing thehuman survivin promoter driving firefly luciferase are treated with thecompound at 5 μM for 24 hrs. The HeLa cells (15,000 cells/well) areplated in 96-well plates. After adhering to the plates, the HeLa cellsare treated with the compound at 5 μM (0.05% DMSO). After 24-hrincubation, survivin promoter activity is assessed using a luciferaseassay to assess the inhibition of transactivation of the survivinpromoter. During the measurement, cell culture medium is removed from a96-well plate and 1×GIo Lysis buffer (Promega) is added to the plate.After 10-min incubation, an equal volume of Bright-Glo Luciferasesubstrate (Promega) is added, and the luminescence signal is detectedwith a 96-well Luminoskan luminescence plate reader (Thermo FisherScientific, Waltham, Mass.) with 5-seconds integration time.

The compound that reduces luciferase expression is retested forreproducibility using the luciferase assay and is also tested forviability. Cell viability is determined using the CellTiter96 aqueousnonradioactive (MTS) assay, where propidium iodide (PI) staining is used(Biovision, Mountain view, Calif.).

The compound that is confirmed to be active in reducing luciferaseexpression is further evaluated as an anti-cancer agent by treatingleukemia cell lines with increasing concentrations of the compound for72 hrs. Cell viability is also measured by the MTS assay. Cell death isevaluated by detecting the presence of a subG1 peak by flow cytometryafter staining cells with PI.

Results are normalized and corrected for systematic errors using the Bscore (Gunter, J. Biomol. Screen. 2003, 8, 624-633). The compound with aB score value lower than 3 times the standard deviation is considered tobe active.

Example 3 Determination of Survivin mRNA and Protein Expression Levelsin HeLa Cells

The survivin mRNA and protein expression levels in wild type HeLa cellsthat are treated with a compound are determined using quantitativereal-time polymerase chain reaction (QRT-PCR) and immunoblotting todetermine its anticancer activity.

For QRT-PCR, cDNAs encoding survivin and glyceraldehyde-3-phosphatedehydrogenase (GAPDH) are amplified using the following primer pairs:survivin, forward, 5′-TTTTCATCGTCGTCCCTAGC-3′ (SEQ ID NO:3); reverse,5′-CGACTCAGATGTGGCAGAAA-3′ (SEQ ID NO:4); and GAPDH, forward,5′-GAAGGTGAAGGTCGGAGTC-3″ (SEQ ID NO:5); reverse,5′-GAAGATGGTGATGGGATTTC-3′ (SEQ ID NO:6). Equal amounts of cDNAs areadded to a prepared master mix (SYBR Green PCR Master mix; AppliedBiosystems, Foster City, Calif.). QRT-PCR is performed on an ABI Prism7700 sequence detection system (Applied Biosystems, Foster City,Calif.). The relative abundance of a transcript is represented by thethreshold cycle of amplification (CT), which is inversely correlated tothe amount of target RNA/first-strand cDNA being amplified. To normalizefor equal amounts of the latter, the transcript levels of the putativehousekeeping gene GAPDH are assayed.

For immunoblotting, total cell lysates are prepared. Cells are washedwith phosphate-buffered saline pH 7.4, and suspended in lysis buffer (10mM Tris, pH 7.4, 150 mM, NaCl, 0.1% Triton X-100, 0.5% sodiumdeoxycholate, and 5 mM EDTA) containing protease inhibitors (Completetablets; Roche, I N). Nuclear extracts are isolated after a cytoplasmprotein extraction by incubating the cells with the cytoplasm buffer onice for 15 min (10 mM HEPES, 10 mM KCl, 0.1 mM EDTA, 0.1 mM EGTA, DTT 1mM, NP40 0.65%, protease inhibitors, pH 7.4) and centrifugation at 4° C.for 1 min at 10,000 g. The pellet is suspended in the lysis buffer (10mM Tris, pH 7.4, 150 mM, NaCl, 0.1% Triton X-100, 0.5% sodiumdeoxycholate, SDS 1.7%, glycerol 5% and 5 mM EDTA) for 30 min and thencentrifuged at 4° C. at maximum speed for 20 min. Protein concentrationsare measured by the Bradford assay. Equal amounts of protein aresubjected to sodium dodecyl sulphate (SDS)-polyacrylamide gels, followedby transfer to polyvinylidene difluoride membranes. Membranes are probedwith polyclonal rabbit anti-human survivin (1 μg/mL) (NOVUS), monoclonalmouse anti-human p53 (0.5 μg/mL), polyclonal rabbit anti-human GR (0.5μg/mL), both from Santa Cruz Biotechnologies, CA; or with mouseanti-human GADPH (Trevigen, Gaithersburg, Md.). Secondary antibodies (GEHealthcare, Chalfont St Giles, United Kingdom) are horseradishperoxidase-conjugated goat anti mouse IgG (1:10,000, v/v) and antirabbit (1:5000, v/v). Detection is performed by the enhanced chemicalluminescence method (Pierce, Rockford, Ill.).

Example 4 Leukemia Stem Cells

Compounds provided herein are tested for their ability to reduce theviability of TEX and M9-ENL1 cells. TEX and M9-ENL1 cells are derivedfrom lineage-depleted human cord blood cells (Lin-CB) transduced withTLS-ERG or MLL-ENL oncogenes, respectively, and display propertiessimilar to leukemia stem cells such as a hierarchal differentiation andmarrow repopulation. TEX and M9-ENL1 cells are treated with compoundsprovided herein at a final concentration of 1 or 5 μM. Seventy-two hoursafter incubation, cell viability is measured by the Alamar Blue assay.

Example 5 Mouse Xenograft Models

Mouse xenograft models are used to evaluate the in vivo anticanceractivity of a compound.

Mouse xenograft models are prepared by injecting MDAY-D2 (MDAY) murineleukemia cells (5×10⁵) intraperitoneally into NOD/SCID mice (OntarioCancer Institute, Toronto, ON); or by inoculating subcutaneously in theflanks of sublethally irradiated NOD-SCID mice (3.5 Gy) with OCI-AML2(2×10⁶), K562 cells (2×10⁶), MDAY-D2, or U937 leukemia cells.

Compound treatment is initiated when tumors reach volumes of 200 mm³ atwhich time mice are randomized to receive 50 mg/kg/day of the compound(treated group) or buffer control (untreated group) for 5 to 7 days.Caliper measurements are performed twice weekly to estimate tumor volume(tumor length×width×0.5236) (Pham et al., Mol. Cancer. Ther. 2004, 3,1239-1248) and differences compared between treated and untreatedgroups. Eight (MDA Y-D2), eleven (OCI-AML2), or thirty (K562) days afterinjection of cells, mice are sacrificed, and the volume and weight ofthe tumors are measured.

Alternatively, primary AML cells are injected intrafemorally into theright femur of sublethally irradiated nude/NOD/SCID female mice. Fourweeks after injection, mice are treated with a compound 5/7 days for 4weeks. At the end of the experiment, the mice are sacrificed, and cellsare flushed from the femurs. Engraftment of human cells into the marrowis assessed by enumerating the percentage of human CD45 cells usingAPC-Cy7-anti-CD45 and flow cytometry. Engrafted cells are confirmed tobe leukemic in origin by the presence of human CD33 and lack of CD19.

Example 6 Cell Proliferation Assay and the Determination of IC₅₀

Adherent Cells

On day 0, cells are seeded at 20,000 cells per well in 100 μL of mediainto individual wells of a 96-well tissue culture plate. The next day,compounds are diluted in 100 μL of media for a total of 200 pt. Eachconcentration of the compounds is prepared at 1000× in DMSO (e.g., for afinal concentration of 20 μM in the assay, the compounds are prepared at20 mM in 100% DMSO). The compounds are then diluted 1:500 in media andadded in the amount of 100 μL to each well for a final concentration of1:1000 with 0.1% DMSO. Each concentration of the compounds is tested intriplicate. Cells are incubated at 37° C. with 5% CO₂. After 72 hours,20 μL of CellTiter 96 Aqueous One Solution Cell Proliferation Assay(Promega) is added to each well. Cells are placed back in the incubator,and the absorbance at 490 nm is read after 2-3 hours. The concentrationof the compounds that decreases the number of metabolically active cellsby 50% is determined and reported as the IC₅₀. “Percent Viability” isdetermined by subtracting the average background value (media only) andexpressed as a ratio to the average value obtained from cells treatedwith only DMSO.

Suspension Cells

Assays with suspension cells are similar except that 40,000-60,000 cellsare added to each well and compounds are added immediately after cellplating.

Example 7 Preparation of Compounds 1 and 4

Compounds 1 and 4 are prepared according to the procedure as describedin Scheme E1.

Example 8 Preparation of Compound 63

Compound 63 is prepared according to the procedure as described inScheme E2.

Example 9 Preparation of Compounds 81 and 162

Compounds 81 and 162 are prepared according to the procedure asdescribed in Scheme E3.

Example 10 Preparation of Compound 243

Compound 63 is prepared according to the procedure as described inScheme E4.

Example 11 Preparation of Compounds 334 to 338

Compounds 334 to 338 are prepared according to the procedure asdescribed in Scheme E5.

Preparation of 6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-yl benzoate 338.To 6-cyclohexyl-1-hydroxy-4-methylpyridin-2(1H)-one (0.5 g) in CH₂Cl₂(20 mL) were added DMAP (0.44 g) and PhCOCl (0.5 mL) at 7° C. After themixture was stirred at 7° C. for 90 min, solvent was partially removedin vacuum. Water (20 mL) and ethyl acetate (20 mL) were added. Theorganic layer was collected and concentrated. The desired compound wasrecrystallized from ethyl acetate and petrelum ether to yield compound338 (0.22 g).

Example 12 Preparation of6-cyclohexyl-1-hydroxy-4-(trifluoromethyl)pyridin-2(1H)-one 54

Compound 54 is prepared according to the procedure as described inScheme E6.

Preparation of cyclohexylcarboxylic chloride. The mixture ofcyclohexylcarboxylic acid (40 g) and SOCl₂ (60 mL) was heated at 30° C.for 30 min and then at 50° C. for 3-5 hrs. The volatile materials wereremoved in vacuum and the residue was used for the next reaction withoutfurther purification.

Preparation of5-(cyclohexanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione A1. ToMeldrum's acid (45 g) in a mixture of pyridine (58 mL) and CH₂Cl₂ (160mL) was added the solution of cyclohexylcarboxylic chloride in CH₂Cl₂(50mL) slowly at about 5-8° C. The reaction mixture was stirred at RTovernight and then at 50° C. for 2 hrs. The reaction mixture was washedwith diluted HCl (pH 5-6) and H₂O. Evaporation of solvent gave crudecompound A1 without further purification.

Preparation of methyl 3-cyclohexyl-3-oxopropanoate A2. A solution ofcompound A1 in MeOH (150 mL) was refluxed to give compound A2 (about 20g) after flash column purification.

Preparation of ethyl 3-chloro-4,4,4-trifluorobut-2-enoate A4. To asolution of compound A3 (40 mL) in CCl₄ (200 mL) was added PCl₅ (52 g).The reaction solution was heated at 50° C. for 8 hrs. After cooled to 0°C., CH₂Cl₂ was added to the reaction solution. The resulted solution waswashed sequentially with ice water and iced Na₂CO₃ solution. Evaporationgave crude compound A4, which was used without further purification.

Preparation of methyl6-cyclohexyl-2-oxo-4-(trifluoromethyl)-2H-pyran-5-carboxylate A5. To asolution of ketoester A2 (16 g) in THF (230 mL) was added NaH (60%) (3.5g) at 5° C. Compound A4 (17.7 g) was then added slowly to the reactionmixture. The reaction mixture was heated at 50° C. for 3-5 hrs and thenRT overnight. Solvents were removed in vacuum and ethyl acetate was thenadded. The organic solution was washed with saturated NaHCO₃ solutionand water. Evaporation of solvents gave a compound A5 (27.7 g).

Preparation of 6-cyclohexyl-4-(trifluoromethyl)-2H-pyran-2-one A5. To amixture of compound A5 (27.7 g) in AcOH (108 mL) was added a premixedsolution of H₂SO₄ (54 mL) and H₂O (54 mL). The solution was then heatedat 120° C. for 4 hrs. AcOH was removed and water (100 mL) was thenadded. The crude material was obtained by extraction with ethyl acetate.Compound A6 (2.38 g) was obtained after flash column purification.

Preparation of6-cyclohexyl-1-hydroxy-4-(trifluoromethyl)pyridin-2(1H)-one 54. Amixture of compound A6 (2.48 g), NH₂OH.HCl (2.6 g), and imidazole (7.8g) was heated at 80° C. for 3 hrs. The solution was acidified to pH 5-6using diluted HCl solution. The mixture was then extracted with ethylacetate twice. Compound 54 (0.3 g) was isolated by evaporation ofsolvent and flash column purification.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

1. A compound of Formula I:

or an enantiomer, a mixture of enantiomers, a mixture of two or morediastereomers, a tautomer, or a mixture of two or more tautomers; or apharmaceutically acceptable salt thereof; wherein: Z is a bond; R¹ is—C(O)R²; R² is (a) hydrogen or deuterium; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₅ aralkyl; or (c)—OR^(1a), —NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c), or—NR^(1a)S(O)₂NR^(1b)R^(1c); R³ and R⁵ are each independently hydrogen,deuterium, or fluoro; R⁴ is —COOH, —CH₂R^(4a), —CH(R^(4a))₂, or—C(R^(4a))₃; wherein R^(4a) is hydrogen, deuterium, fluoro, or hydroxyl;R⁶ is hydrogen, deuterium, fluoro, or hydroxyl; each R⁷ is independently(a) deuterium, halo, cyano, nitro, or guanidine; (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₅ aralkyl; or(c) —C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c),—C(NR^(1a))NR^(1b)R^(1c), —OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a),—OC(O)NR^(1b)R^(1c), —OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a),—OS(O)₂R^(1a), —OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c),—NR^(1b)R^(1c), —NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d),—NR^(1a)C(O)NR^(1b)R^(1c), —NR^(1a)C(═NR^(1d))NR^(1b)R^(1c),—NR^(1a)S(O)R^(1d), —NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —SR^(1a), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); or two R⁷ are linkedtogether to form a bond, —O—, —NR⁸—, —S—, C₁₋₆ alkylene, C₁₋₆heteroalkylene, C₂₋₆ alkenylene, or C₂₋₆ heteroalkenylene; R⁸ isindependently (a) hydrogen or deuterium; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₅ aralkyl; or (c)—C(O)R^(1a), —C(O)OR^(1a), —C(O)NR^(1b)R^(1c), —C(NR^(1a))NR^(1b)R^(1c),—OR^(1a), —OC(O)R^(1a), —OC(O)OR^(1a), —OC(O)NR^(1b)R^(1c),—OC(═NR^(1a))NR^(1b)R^(1c), —OS(O)R^(1a), —OS(O)₂R^(1a),—OS(O)NR^(1b)R^(1c), —OS(O)₂NR^(1b)R^(1c), —NR^(1b)R^(1c),—NR^(1a)C(O)R^(1d), —NR^(1a)C(O)OR^(1d), —NR^(1a)C(O)NR^(1b)R^(1c),—NR^(1a)C(═NR^(1d))NR^(1b)R^(1c), —NR^(1a)S(O)R^(1d),—NR^(1a)S(O)₂R^(1d), —NR^(1a)S(O)NR^(1b)R^(1c),—NR^(1a)S(O)₂NR^(1b)R^(1c), —S(O)R^(1a), —S(O)₂R^(1a),—S(O)NR^(1b)R^(1c), or —S(O)₂NR^(1b)R^(1c); each R^(1a), R^(1b), R^(1c),and R^(1d) is independently hydrogen, deuterium, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₅ aralkyl; mis an integer of 2; and n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7;wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene,heteroalkenylene, alkynyl, cycloalkyl, aryl, and aralkyl, is optionallysubstituted with one or more substituents Q, where each Q isindependently selected from (a) deuterium, cyano, halo, and nitro; (b)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, andC₇₋₁₅ aralkyl, each of which is further optionally substituted with oneor more substituents Q^(a); and (c) —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O)R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen ordeuterium; or (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₅ aralkyl each optionally substitutedwith one or more substituents Q^(a); wherein each Q^(a) is independentlyselected from the group consisting of (a) deuterium, cyano, halo, andnitro; (b) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl,C₆₋₁₄ aryl, and C₇₋₁₅ aralkyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(f), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen ordeuterium; or (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, or C₇₋₁₅ aralkyl.
 2. The compound of claim 1,wherein n is
 0. 3. The compound of claim 1 having the structure ofFormula VI.


4. The compound of claim 1, wherein R² is C₁₋₆ alkyl.
 5. The compound ofclaim 1, wherein R² is C₆₋₁₄ aryl.
 6. The compound of claim 5, whereinR² is phenyl.
 7. The compound of claim 1, wherein R³ is hydrogen.
 8. Thecompound of claim 1, wherein R⁵ is hydrogen.
 9. The compound of claim 1,wherein R⁴ is —C(R^(4a))₃.
 10. The compound of claim 9, wherein R^(4a)is hydrogen.
 11. The compound of claim 9, wherein R^(4a) is deuterium.12. The compound of claim 9, wherein R^(4a) is fluoro.
 13. The compoundof claim 1, wherein R⁴ is methyl or trifluoromethyl.
 14. The compound ofclaim 1, wherein R⁶ is hydrogen.
 15. The compound of claim 1, wherein R¹is —C(O)—C₆₋₁₄ aryl; R³, R⁵, and R⁶ are hydrogen; R⁴ is C₁₋₆ alkyl; m is2; and n is 0; where the alkyl and aryl are optionally substituted withone or more substituents Q.
 16. The compound of claim 1, wherein R¹ isbenzoyl; R³, R⁵, and R⁶ are hydrogen; R⁴ is methyl; m is 2; and n is 0;where the methyl and benzoyl are optionally substituted with one or moresubstituents Q.
 17. The compound of claim 1, wherein R¹ is benzoyl; R³,R⁵, and R⁶ are hydrogen; R⁴ is methyl or trifluoromethyl; m is 2; and nis
 0. 18. The compound of claim 1, selected from the group consistingof:

and tautomers and mixtures of two or more tautomers thereof; andpharmaceutically acceptable salts thereof.
 19. The compound of claim 18,wherein the compound is 6-cyclohexyl-4-methyl-2-oxopyridin-1(2H)-ylbenzoate, or a tautomer or a mixture of two or more tautomer thereof; ora pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising the compound of claim 1, or an enantiomer, amixture of enantiomers, a mixture of two or more diastereomers, atautomer, or a mixture of two or more tautomers thereof; or apharmaceutically acceptable salt thereof; and one or morepharmaceutically acceptable carriers or excipients.
 21. Thepharmaceutical composition of claim 20, wherein the composition isformulated for single dose administration.
 22. The pharmaceuticalcomposition of claim 20, wherein the composition is formulated as anoral, parenteral, or intravenous dosage form.
 23. The pharmaceuticalcomposition of claim 22, wherein the oral dosage form is a tablet,capsule, or solution.